Compounds which inhibit neuronal exocytosis

ABSTRACT

Compounds of general formula (I): R 1 —W n —X m -AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -AA 7 -Y p —Z q —R 2 , their stereoisomers, mixtures thereof and/or their cosmetically or pharmaceutically acceptable salts, preparation processes, cosmetic or pharmaceutical compositions which contain them and their use in medicine, particularly in the treatment and/or prevention of pain, inflammation, itching, neurological, compulsive and/or neuropsychiatric diseases and/or disorders and in processes of treatment and/or care of the skin, hair and/or mucous membranes mediated by neuronal exocytosis.

This application claims the benefit of PCT/EP2013/057656, filed Apr. 12,2013, and EP12382144.9, filed Apr. 13, 2012, EP12382303.1, filed Jul.27, 2012, U.S. Provisional Application Ser. No. 61/652,647, filed May29, 2012, and U.S. Provisional Application Ser. No. 61/746,888, filedDec. 28, 2012, from which the PCT application claims priority, thedisclosures of all of which are incorporated herein by reference intheir entireties.

FIELD OF THE INVENTION

This invention refers to compounds capable of inhibiting neuronalexocytosis and cosmetic or pharmaceutical compositions which containthese compounds useful in the treatment of those conditions, disordersand/or diseases which require the inhibition of neuronal exocytosis,such as muscle spasticity, pain, inflammation, perspiration, facialasymmetry and/or facial wrinkles, preferably expression wrinkles.

BACKGROUND OF THE INVENTION

Botulinum toxins (also known as botulinum neurotoxins) are neurotoxinsproduced by the gram-positive bacteria Clostridium botulinum. They actby causing the paralysis of the muscles through the inhibition of therelease of acetylcholine in the presynaptic axon terminal of theneuromuscular junction (synaptic transmission), thus preventing nervetransmission and muscle contraction. The paralyzing effects of themuscles of the botulinum toxin have been used both for therapeuticpurposes as well as for cosmetic effects. The controlled administrationof the botulinum toxin has been used for the treatment of a wide rangeof conditions, disorders and diseases, such as disorders and diseases ofthe urinary bladder (EP 2273976 A2), premature ejaculation (US2011/052636 A1), priapism (U.S. Pat. No. 6,776,991 B2), ulcers andgastroesophageal reflux (U.S. Pat. No. 7,238,357 B2), disorders anddiseases associated with hyper- and hypothyroidism (U.S. Pat. No.6,740,321 B2), primary hyperparathyroid disorders and diseases (U.S.Pat. No. 6,974,793 B2), perspiration and hyperhidrosis (U.S. Pat. No.6,974,578 B2 and U.S. Pat. No. 6,683,049 B2), inflammatory eye disordersand diseases (U.S. Pat. No. 7,465,458 B2 and U.S. Pat. No. 7,220,422B2), strabismus (U.S. Pat. No. 6,841,156), otic disorders and diseases(U.S. Pat. No. 6,265,379 B2 and U.S. Pat. No. 6,358,926 B2), excesscerumen secretion (US 2010/028385), neuropsychiatric disorders anddiseases such as Alzheimer's, anxiety, schizophrenia, mania, depression(U.S. Pat. No. 7,811,587 B2), different compulsive disorders anddiseases such as obsessions, compulsive skin picking, Tourette'ssyndrome, trichotillomania (U.S. Pat. No. 7,393,537 B2), cerebralparalysis (U.S. Pat. No. 6,939,852 B2), gonadotropin-related disordersand diseases (WO 02/074327), different cancers (U.S. Pat. No. 6,139,845B2, U.S. Pat. No. 7,838,007 B2), neoplasms (U.S. Pat. No. 7,709,440 B2),different types of pain including headaches, migraines, fibromyalgia,arthritis or neuropathic pain among others (US 2010/266638, U.S. Pat.No. 7,811,586 B2, U.S. Pat. No. 7,704,524 B2, U.S. Pat. No. 7,704,511B2, U.S. Pat. No. 7,468,189 B2, U.S. Pat. No. 7,255,866 B2, U.S. Pat.No. 7,091,176 B2, U.S. Pat. No. 6,887,476 B2, U.S. Pat. No. 6,869,610B2, U.S. Pat. No. 6,838,434 B2, U.S. Pat. No. 6,641,820 B2, U.S. Pat.No. 6,623,742 B2, U.S. Pat. No. 6,565,870 B1, U.S. Pat. No. 6,500,436B1, U.S. Pat. No. 6,458,365 B1, U.S. Pat. No. 6,423,319 B1, U.S. Pat.No. 6,113,915 A and U.S. Pat. No. 5,714,468 A), neurogenic inflammation(U.S. Pat. No. 6,063,768 B2), different disorders and diseases of theautonomic nervous system such as otitis and sinusoidal disorders (U.S.Pat. No. 5,766,605 A), disorders and diseases of the smooth muscle (U.S.Pat. No. 5,437,291 A), nerve impingements (US 2003/0224019), epilepsy(U.S. Pat. No. 7,357,934 B2), dystonia (U.S. Pat. No. 6,872,397 B2),trembling (U.S. Pat. No. 6,861,058 B2), Parkinson's disease (U.S. Pat.No. 6,620,415 B2), dizziness (U.S. Pat. No. 7,270,287 B2), osteoporosis(WO 2011/038015), different disorders and diseases of the skin such ascalluses, warts, ulcers and lesions on the skin (U.S. Pat. No. 8,048,423B2, US 2011/206731), psoriasis and dermatitis (U.S. Pat. No. 5,670,484A), vascular hyperreactivity and rosacea (WO 2010/114828), acne (WO03/011333), hair growth and maintenance (U.S. Pat. No. 6,299,893 B1),facial wrinkles (U.S. Pat. No. 7,255,865 B2), ptosis of the eyebrows andforehead (US 2011/280978) or drooping mouth corners (U.S. Pat. No.6,358,917 B1) among others.

However, the toxicity inherent in botulinum toxin causes itsadministration, in a wide range of doses, to result in undesiredsecondary effects, such as immunogenic responses, cephalalgias, nausea,paralysis or muscle weakness, respiratory failure, and in more extremecases even the death of the subject treated [FDA News, Feb. 8, 2008,“FDA Notifies Public of Adverse Reactions Linked to Botox Use”; Coté, T.R. et al. “Botulinum toxin type A injections: Adverse events reported tothe US Food and Drug Administration in therapeutic and cosmetic cases”J. Amer. Acad. Derm. 2005, 53 (3), 407-415]. These severe secondaryeffects, together with the high cost of the treatment, seriously limitsthe application of botulinum toxin with therapeutic or cosmeticpurposes, being relegated to chronic applications and/or diseases forwhich there is no suitable treatment. There is, therefore, a pressingneed to develop molecules which imitate the paralyzing effects ofbotulinum toxins but which are equipped with much simpler and morestable molecular structures that do not induce immune reactions, andwhose cost of production is affordable. Molecules of a peptide naturecomply with these properties.

At a molecular level, botulinum toxins are proteases which degradeneuronal proteins that are involved in the exocytosis mechanismactivated by the calcium ion [Schiavo G. et al. “Bases Moleculares deltétanos y del botulismo” Investigación y Ciencia 1996, 234, 46-55;Montecucco C. and Schiavo G. “Mechanism of action of tetanus andbotulinum neurotoxins” Mol. Microbiol. 1994, 13, 1-8; Schiavo G. et al.“Tetanus and botulinum neurotoxins are zinc proteases specific forcomponents of the neuroexocytosis apparatus” Ann. NY Acad. Sci. 1994,710, 65-75]. For example, botulinum toxin A, the most commonly used inclinics to treat the symptomatology of spasmodic diseases and incosmetics due to its applications in the elimination of facial wrinklesand facial asymmetry, breaks down the neuronal protein SNAP-25. Thisprotein SNAP-25 plays a key role in neurosecretion since it is involvedin the formation of a protein complex (known by the name of SNARE orfusion complex) which manages and controls the release of acetylcholineaccumulated in vesicles. The nucleus of this fusion complex is comprisedof the proteins SNAP-25 and syntaxin, located in the presynaptic plasmamembrane, and the synaptobrevin protein of the VAMP family of proteins,located in the vesicular plasma membrane [Calakos N. and Scheller R. H.“Synaptic vesicle biogenesis, docking and fusion: a moleculardescription” Physiol. Rev. 1996, 76, 1-29; Sutton R. B. et al. “Crystalstructure of a SNARE complex involved in synaptic exocytosis at 2.4 Åresolution” Nature 1998, 395, 347-353]. The principal function of thefusion complex is to bring the neurotransmitter (acetylcholine) loadedvesicle closer to and place it in contact with the presynaptic plasmamembrane [Calakos N. and Scheller R. H. “Synaptic vesicle biogenesis,docking and fusion: a molecular description” Physiol. Rev. 1996, 76,1-29; Sutton R. B. et al. “Crystal structure of a SNARE complex involvedin synaptic exocytosis at 2.4 Å resolution” Nature 1998, 395, 347-353].In this way, in response to an increase in the concentration of calcium,the fusion of both plasma membranes will be favored, thus producing therelease of the neurotransmitter. Therefore, this vesicle docking andfusion protein SNARE complex constitutes a key target for controllingneurosecretion. The truncation of any of the proteins which form thefusion complex prevents their assembling and, therefore, inhibitsvesicle release and inhibits neuronal exocytosis.

It is known in the prior art that certain peptides derived from theprotein sequences which form the SNARE complex are capable of inhibitingneuronal exocytosis, such as peptides derived from the amino andcarboxy-terminal domains of the protein SNAP-25 [Apland J. P. et al.“Peptides that mimic the carboxy-terminal domain of SNAP-25 blockacetylcholine release at an aplysia synapse” J. Appl. Toxicol. 1999, 19,Suppl. 1: S23-S26; Mehta P. P. et al. “SNAP-25 and synaptotagmininvolvement in the final Ca ²⁺-dependent triggering of neurotransmitterexocytosis” Proc. Natl. Acad. Sci. USA 1996, 93, 10471-10476;Ferrer-Montiel A. V. et al. “The 26-mer peptide released from cleavageby botulinum neurotoxin E inhibits vesicle docking” FEBS Lett. 1998,435, 84-88; Gutierrez L. M. et al. “A peptide that mimics thecarboxy-terminal domain of SNAP-25 blocks Ca ²⁺-dependent exocytosis inchromaffin cells” FEBS Lett. 1995, 372, 39-43; Gutierrez L. M. et al. “Apeptide that mimics the C-terminal sequence of SNAP-25 inhibitssecretory vesicle docking in chromaffin cells” J. Biol. Chem. 1997, 272,2634-2639; Blanes-Mira C et al. “Small peptides patterned after theN-terminus domain of SNAP-25 inhibit SNARE complex assembly andregulated exocytosis” J. Neurochem. 2004, 88, 124-135], the peptidesderived from the sequence of syntaxin amino acids [Martin F. et al.“Inhibition of insulin release by synthetic peptides show that the H3region at the C-terminal domain of syntaxin-1 is crucial for Ca ²⁺-butnot for guanosine 5′-[gammathio]thriphosphate-induced secretion”Biochem. J. 1996, 320, 201-205], of the synaptobrevin [Cornille F.“Inhibition of neurotransmitter release by synthetic prolinerichpeptides shows that the N-terminal domain of vesicle-associated membraneprotein/synaptobrevin is critical for neuro-exocytosis” J. Biol. Chem.1995, 270, 16826-16830], of the synaptotagmin [Mehta P. P. et al.“SNAP-25 and synaptotagmin involvement in the final Ca ²⁺-dependenttriggering of neurotransmitter exocytosis” Proc. Natl. Acad. Sci. USA1996, 93, 10471-10476] and of the protein snapin [Ilardi J. M. et al.“Snapin: A SNARE associated protein implicated in synaptic transmission”Nat. Neurosci. 1999, 2, 119-124]. Similarly, synthetic peptides obtainedby rational design or by searching synthetic libraries which are capableof inhibiting neuronal exocytosis by interfering in the formation of theSNARE complex have also been described [Blanes-Mira C. et al.“Identification of SNARE complex modulators that inhibit exocytosis forman α-helixconstrained combinatorial library” Biochem J. 2003, 375,159-166].

The industrial application of this type of compounds has been limited.The document EP 2318033 A2 describes the use of peptides derived fromSNAP-25 for the treatment of pain and inflammation, and the document EP1856139 A2 describes the use of peptides derived from SNAP-25 chemicallymodified to increase their bioavailability for the treatment ofdifferent diseases for which the treatment with botulinum toxin hasshown effectiveness, among them the treatment of hyperhidrosis.Similarly, the cosmetic industry has made significant efforts to developcompounds which imitate the action of botulinum toxins with use in thetreatment and prevention of the formation of expression wrinkles[Blanes-Mira C. et al. “A synthetic hexapeptide (Argireline®) withanti-wrinkle activity” Int. J. Cosmetic Sci. 2002, 24, 303-310]. Inparticular, peptides derived from the amino terminal fragment of theprotein SNAP-25 which have anti-wrinkle effects are described in thedocuments EP 1180524 A1 and EP 2123673 A1, international application WO97/34620 also describes peptides derived from the sequence of aminoacids of the protein SNAP-25, in particular from its carboxy-terminalregion, or from the synaptobrevin or the syntaxin capable of inhibitingneuronal exocytosis, and international application WO 2011/048443describes peptides derived from the subunit c of the membrane componentof V-ATPase capable of inhibiting neuronal exocytosis through itsbonding to synaptobrevin and its potential application as anti-wrinkletreatment.

Thus, this invention provides an alternative to the existing needs andcomprises the discovery of peptide sequences not derived from theprotein SNAP-25 which are capable of inhibiting neuronal exocytosis.

DESCRIPTION OF THE INVENTION

This invention provides an alternative to the above-mentioned problem.Surprisingly, the authors of this invention have found that neuronalexocytosis can be inhibited by certain compounds not derived from theprotein SNAP-25 and which are an alternative to the existing compoundsin the prior art. These compounds are useful for the treatment and/orcare of conditions, disorders and/or diseases which improve or areprevented by the inhibition of neuronal exocytosis.

Definitions

In order to facilitate the comprehension of this invention, the meaningsof some terms and expressions as they are used in the context of theinvention are included.

In the context of this invention “skin” is understood as the layerswhich comprise it, from the uppermost layer or stratum corneum to thelowermost layer or hypodermis, both inclusive. These layers are composedof different types of cells such as keratinocytes, fibroblasts,melanocytes, mastocytes, neurones and/or adipocytes, among others. Theterm “skin” also comprises the scalp.

The term “treatment”, as used in the context of this specification whenit is not accompanied by the qualifications “cosmetic, non-therapeutic”,means the administration of a compound according to the invention toalleviate or eliminate a disease or disorder or reduce or eliminate oneor more symptoms associated with this disease or disorder. The term“treatment” also covers the ability to alleviate or eliminate thephysiological consequences of the disease or disorder.

When the term “treatment” is accompanied by the qualifications“cosmetic, non-therapeutic” they refer to the application of thecompound to the skin, hair and/or mucous membranes in particular withthe aim of improving the cosmetic qualities of the skin, hair and/ormucous membranes such as and not restricted to, their level ofhydration, elasticity, firmness, shine, tone or texture, among others.The term “care” in this invention refers to the maintenance of thequalities of the skin, hair and/or mucous membranes. These qualities aresubject to improvement and maintained through a cosmetic treatmentand/or care of the skin, hair and/or mucous membranes both in healthysubjects as well as those which present diseases and/or disorders of theskin and/or mucous membranes, such as and not restricted to, ulcers andlesions on the skin, psoriasis, dermatitis, acne or rosacea, amongothers.

The term “prevention”, as used in this invention, refers to the abilityof a compound of the invention to prevent the appearance or developmentof a disease or disorder before its appearance.

In the context of this invention, the term “aging” refers to the changesexperienced by the skin with age (chronoaging) or through exposure tothe sun (photoaging) or to extreme environmental climatic conditions ofcold or wind, chemical contaminants or pollutants, and includes all theexternal visible and/or perceptible changes through touch, such as andnot restricted to, the development of discontinuities on the skin suchas wrinkles, fine lines, expression lines, stretch marks, furrows,irregularities or roughness, increase in the size of pores, loss ofhydration, loss of elasticity, loss of firmness, loss of smoothness,loss of the capacity to recover from deformation, loss of resilience,sagging of the skin such as sagging cheeks, the appearance of bags underthe eyes or the appearance of a double chin, among others, changes tothe color of the skin such as marks, reddening, bags or the appearanceof hyperpigmented areas such as age spots or freckles among others,anomalous differentiation, hyperkeratinization, elastosis, keratosis,hair loss, orange peel skin, loss of collagen structure and otherhistological changes of the stratum corneum, of the dermis, epidermis,vascular system (for example the appearance of spider veins ortelangiectasias) or of those tissues close to the skin, among others.The term “photoaging” groups together the set of processes due to theprolonged exposure of the skin to ultraviolet radiation which result inthe premature aging of the skin, and it presents the same physicalcharacteristics as aging, such as and not restricted to, flaccidity,sagging, changes to the color or irregularities in the pigmentation,abnormal and/or excessive keratinization. The sum of severalenvironmental factors such as exposure to tobacco smoke, exposure topollution, and climatic conditions such as cold and/or wind alsocontributes to the aging of the skin.

In this description the abbreviations used for amino acids follow therecommendations of the 1983 IUPAC-IUB Commission of BiochemicalNomenclature specified in Eur. J. Biochem., (1984), 138, 937.

Thus, for example, Phe represents NH₂—CH(CH₂—C₅H₆)—COOH, Phe- representsNH₂—CH(CH₂—C₅H₆)—CO—, -Phe represents —NH—CH(CH₂—C₅H₆)—COOH and -Phe-represents —NH—CH(CH₂—C₅H₆)—CO—. Therefore, the hyphen, which representsthe peptide bond, eliminates the OH in the 1-carboxyl group of the aminoacid (represented here in the conventional non-ionized form) whensituated to the right of the symbol, and eliminates the H of the 2-aminogroup of the amino acid when situated to the left of the symbol; bothmodifications can be applied to the same symbol (see Table 1).

TABLE 1 Structures of the amino acid residues and their nomenclature inone and three-letter code Name Residue Symbol Residue Asparaginyl -Asn-N

Glutaminyl -Gln- Q

Histidyl -His- H

Arginyl -Arg- R

Lysyl -Lys- K

Tryptophyl -Trp- W

Tyrosyl -Tyr- Y

Phenylalanyl -Phe- F

Leucyl -Leu- L

Methionyl -Met- M

Valyl -Val- V

Isoleucyl -Ile- I

Glutamyl -Glu- E

Aspartyl -Asp- D

Prolyl -Pro- P

Glycyl -Gly- G

Alanyl -Ala- A

Methionyl (sulfoxide) -MetO-

Methionyl (sulfone) -MetO₂-

The abbreviation “-MetO—” is used in this invention to designate theamino acid residue methionyl(sulfoxide). The amino acid residuemethionyl(sulfoxide) can be incorporated into the compounds of theinvention using the commercial amino acid methionine(sulfoxide) or canbe obtained in situ in the compounds of the invention by oxidation ofthe methionyl residue.

The abbreviation “-MetO₂—” is used in this invention to designate theamino acid residue methionyl(sulfone). The amino acid residuemethionyl(sulfone) can be incorporated into the compounds of theinvention using the commercial amino acid methionine(sulfone) or can beobtained in situ in the compounds of the invention by oxidation of themethionyl residue or the methionyl(sulfoxide) residue.

The abbreviation “Ac-” is used in this description to designate theacetyl group (CH₃—CO—), the abbreviation “Palm-” is used to designatethe palmitoyl group (CH₃—(CH₂)₁₄—CO—) and the abbreviation “Myr-” isused to designate the myristoyl group (CH₃—(CH₂)₁₂—CO—).

The term “non-cyclic aliphatic group” is used in this invention to coveralkyl, alkenyl and alkynyl groups, linear or branched.

The term “alkyl group” refers to a linear or branched saturated groupwhich has between 1 and 24, preferably between 1 and 16, more preferablybetween 1 and 14, even more preferably between 1 and 12, yet morepreferably 1, 2, 3, 4, 5 or 6 carbon atoms and is bound to the rest ofthe molecule by a simple bond, including, for example and not restrictedto, methyl, ethyl, isopropyl, isobutyl, tert-butyl, heptyl, octyl,decyl, dodecyl, lauryl, hexadecyl, octadecyl, amyl, 2-ethylhexyl,2-methylbutyl, 5-methylhexyl and similar.

The term “alkenyl group” refers to a group, linear or branched, whichhas between 2 and 24, preferably between 2 and 16, more preferablybetween 2 and 14, even more preferably between 2 and 12, yet morepreferably 2, 3, 4, 5 or 6 carbon atoms, with one or more doublecarbon-carbon bonds, preferably with 1, 2 or 3 double carbon-carbonbonds, conjugated or unconjugated, which is bound to the rest of themolecule by a simple bond, including, for example and not restricted to,the vinyl group (—CH₂═CH₂), allyl (—CH₂—CH═CH₂), oleyl, linoleyl andsimilar.

The term “alkynyl group” refers to a group, linear or branched, whichhas between 2 and 24, preferably between 2 and 16, more preferablybetween 2 and 14, even more preferably between 2 and 12, yet morepreferably 2, 3, 4, 5 or 6 carbon atoms, with one or more triplecarbon-carbon bonds, preferably 1, 2 or 3 triple carbon-carbon bonds,conjugated or unconjugated, which is bound to the rest of the moleculeby a simple bond, including, for example and not restricted to, theethynyl group, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,pentynyl, such as 1-pentynyl, and similar. The alkynyl groups can alsocontain one or more double carbon-carbon bonds, including for exampleand not restricted to, the group but-1-en-3-ynyl, pent-4-en-1-ynyl andsimilar.

The term “alycyclic group” is used in this invention to cover, forexample and not restricted to, cycloalkyl or cycloalkenyl orcycloalkynyl groups.

The term “cycloalkyl” refers to a saturated mono- or polycyclicaliphatic group which has between 3 and 24, preferably between 3 and 16,more preferably between 3 and 14, even more preferably between 3 and 12,yet more preferably 3, 4, 5 or 6 carbon atoms and is bound to the restof the molecule by a simple bond, including, for example and notrestricted to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, methyl cyclohexyl, dimethyl cyclohexyl, octahydroindene,decahydronaphthalene, dodecahydrophenalene and similar.

The term “cycloalkenyl” refers to a non-aromatic mono- or polycyclicaliphatic group which has between 5 and 24, preferably between 5 and 16,more preferably between 5 and 14, even more preferably between 5 and 12,yet more preferably 5 or 6 carbon atoms, with one or more doublecarbon-carbon bonds, preferably 1, 2 or 3 double carbon-carbon bonds,conjugated or unconjugated, bound to the rest of the molecule by asimple bond, including, for example and not restricted to, thecyclopent-1-en-1-yl group and similar.

The term “cycloalkynyl” refers to a non-aromatic mono- or polycyclicaliphatic group which has between 8 and 24, preferably between 8 and 16,more preferably between 8 and 14, even more preferably between 8 and 12,yet more preferably 8 or 9 carbon atoms, with one or more triplecarbon-carbon bonds, preferably 1, 2 or 3 triple carbon-carbon bonds,conjugated or unconjugated, bound to the rest of the molecule by asimple bond, including, for example and not restricted to, thecyclooct-2-in-1-yl group and similar. The cycloalkynyl groups can alsocontain one or more double carbon-carbon bonds, including for exampleand not restricted to, the cyclooct-4-en-2-ynyl group and similar.

The term “aryl group” refers to an aromatic group which has between 6and 30, preferably between 6 and 18, more preferably between 6 and 10,even more preferably between 6 or 10 carbon atoms, which comprises 1, 2,3 or 4 aromatic rings, bound by a carbon-carbon bond or condensed,including, for example and not restricted to, phenyl, naphthyl,diphenyl, indenyl, phenanthryl or anthranyl, among others; or an aralkylgroup.

The term “aralkyl group” refers to an alkyl group substituted by anaromatic group, with between 7 and 24 carbon atoms and including, forexample and not restricted to, —(CH₂)₁₋₆-phenyl, —(CH₂)₁₋₆-(1-naphthyl),—(CH₂)₁₋₆-(2-naphthyl), —(CH₂)₁₋₆—CH(phenyl)₂ and similar.

The term “heterocyclyl group” refers to a hydrocarbonated ring of 3-10members, in which one or more of the atoms in the ring, preferably 1, 2or 3 of the atoms in the ring, is a different element to carbon, such asnitrogen, oxygen or sulfur and can be saturated or unsaturated. For thepurposes of this invention, the heterocycle can be a monocyclic,bicyclic or tricyclic system, which can include systems of condensedrings; and the nitrogen, carbon or sulfur atoms can optionally beoxidized in the radical heterocycle; the nitrogen atom can optionally bequaternized; and the radical heterocyclyl can be partially or completelysaturated or aromatic. The greatest preference is for the termheterocyclyl to refer to a ring of 5 or 6 members. Examples of saturatedheterocyclic groups are dioxane, piperidine, piperazine, pyrrolidine,morpholine and thiomorpholine. Examples of aromatic heterocyclic groups,also known as heteroaromatic groups are pyridine, pyrrol, furan,thiophene, benzofuran, imidazoline, quinolein, quinoline, pyridazine andnaphthyridine.

The term “heteroarylalkyl group” refers to an alkyl group substituted bya substituted or unsubstituted aromatic heterocyclyl group, the alkylgroup having from 1 to 6 carbon atoms and the aromatic heterocyclylgroup between 2 and 24 carbon atoms and from 1 to 3 atoms other thancarbon and including, for example and not restricted to,—(CH₂)₁₋₆-imidazolyl, —(CH₂)₁₋₆-triazol, —(CH₂)₁₋₆-thienyl,—(CH₂)₁₋₆-furyl, —(CH₂)₁₋₆-pyrrolidinyl and similar.

As is understood in this technical field, there can be a certain levelof substitution of the aforementioned groups. Therefore, there can besubstitution in any of the groups of this invention where specificallystated. The references in this document to substituted groups in thegroups of this invention indicate that the specified radical can besubstituted in one or more positions available by one or moresubstituents, preferably in 1, 2 or 3 positions, more preferably in 1 or2 positions, yet more preferably in 1 position. These substituentsinclude, alkyl C₁-C₄; hydroxyl; alcoxyl C₁-C₄; amino; aminoalkylcarbonyloxyl C₁-C₄; oxycarbonyl C₁-C₄; halogen such as fluoride,chlorine, bromine and iodine; cyano; nitro; azide; alkylsulfonyl C₁-C₄;thiol; alkylthio C₁-C₄; aryloxyl such as phenoxyl;—NR_(b)(C═NR_(b))NR_(b)R_(c); wherein R_(b) and R_(c) are independentlyselected from the group formed by H, alkyl C₁-C₄, alkenyl C₂-C₄, alkynylC₂-C₄, cycloalkyl C₃-C₁₀, aryl C₆-C₁₈, aralkyl C₇-C₁₇, heterocyclyl of3-10 members or protective group of the amino group.

Compounds in the Invention

A first aspect of the invention refers to a compound of general formula(I):R₁—W_(n)—X_(m)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-AA₇-Y_(p)—Z_(q)—R₂  (I)its stereoisomers, mixtures thereof and/or its cosmetically orpharmaceutically acceptable salts, characterized in that:

-   -   AA₁ is selected from the group formed by -Arg-, -His-, -Lys-,        -Gln-, -Asn-, -Glu- and -Asp-;    -   AA₂ is selected from the group formed by -His-, -Gln-, -Asn-,        -Glu- and -Asp-;    -   AA₃ is selected from the group formed by -Leu-, -Ile-, -Phe- and        -Tyr-;    -   AA₄ is selected from the group formed by -Lys-, -His-, -Arg-,        -Gln-, -Leu-, -Ile-, -Met-, -MetO— and -MetO₂—;    -   AA₅ is selected from the group formed by -Arg-, -His-, -Lys-,        -Gln-, -Asn-, -Glu- and -Asp-;    -   AA₆ is selected from the group formed by -Phe-, -Trp-, -Ile- and        -Val-;    -   AA₇ is selected from the group formed by -Met-, -MetO— and        -MetO₂—;    -   W, X, Y, Z are amino acids and are independently selected from        amongst themselves;    -   n, m, p and q are independently selected from amongst themselves        and have a value of 0 or 1;    -   n+m+p+q is smaller or equal to 2;    -   with the condition that it is not        Trp-Lys-Lys-His-Leu-Leu-Lys-Ile-Met (SEQ ID NO:111);    -   R₁ is selected from the group formed by H, a polymer derived        from polyethylene glycol, a non-cyclic substituted or        unsubstituted aliphatic group, substituted or unsubstituted        alicyclyl, substituted or unsubstituted heterocyclyl,        substituted or unsubstituted heteroarylalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted aralkyl and        R₅—CO—, wherein R₅ is selected from the group formed by H, a        non-cyclic substituted or unsubstituted aliphatic group,        substituted or unsubstituted alicyclyl, substituted or        unsubstituted aryl, substituted or unsubstituted aralkyl,        substituted or unsubstituted heterocyclyl and substituted or        unsubstituted heteroarylalkyl;    -   R₂ is selected from the group formed by —NR₃R₄, —OR₃ and —SR₃,        wherein R₃ and R₄ are independently selected from the group        formed by H, a polymer derived from polyethylene glycol, a        non-cyclic substituted or unsubstituted aliphatic group,        substituted or unsubstituted alicyclyl, substituted or        unsubstituted heterocyclyl, substituted or unsubstituted        heteroarylalkyl, substituted or unsubstituted aryl, and        substituted or unsubstituted aralkyl; and    -   R₁ and R₂ are not α-amino acids.

Groups R₁ and R₂ are bound to the amino-terminal (N-terminal) andcarboxy-terminal (C-terminal) ends of the peptide sequencesrespectively.

In accordance with a preferred embodiment of this invention R₁ isselected from the group formed by H, a polymer derived from polyethyleneglycol and R₅—CO—, wherein R₅ is selected from the group formed bysubstituted or unsubstituted alkyl radical C₁-C₂₄, substituted orunsubstituted alkenyl C₂-C₂₄, substituted or unsubstituted alkynylC₂-C₂₄, substituted or unsubstituted cycloalkyl C₃-C₂₄, substituted orunsubstituted cycloalkenyl C₅-C₂₄, substituted or unsubstitutedcycloalkynyl C₈-C₂₄, substituted or unsubstituted aryl C₆-C₃₀,substituted or unsubstituted aralkyl C₇-C₂₄, substituted orunsubstituted heterocyclyl ring of 3-10 members, and substituted orunsubstituted heteroarylalkyl of 2 to 24 carbon atoms and 1 to 3 atomsother than carbon and an alkyl chain of 1 to 6 carbon atoms and R₅—CO—is not an α-amino acid. More preferably, R₁ is selected from the groupformed by H, a polymer derived from polyethylene glycol with a molecularweight comprised between 200 and 35000 Daltons, acetyl, tert-butanoyl,prenyl, hexanoyl, 2-methylhexanoyl, cyclohexanecarboxyl, octanoyl,decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl and linoleoyl.Even more preferably, R₁ is H, acetyl, lauroyl, myristoyl or palmitoyl.In an even more preferred embodiment, R₁ is acetyl or palmitoyl.

In accordance with another preferred embodiment, R₂ is selected from thegroup formed by —NR₃R₄, —OR₃, —SR₃, wherein R₃ and R₄ are independentlyselected from the group formed by H, a polymer derived from polyethyleneglycol, substituted or unsubstituted alkyl C₁-C₂₄, substituted orunsubstituted alkenyl C₂-C₂₄, substituted or unsubstituted alkynylC₂-C₂₄, substituted or unsubstituted cycloalkyl C₃-C₂₄, substituted orunsubstituted cycloalkenyl C₅-C₂₄, substituted or unsubstitutedcycloalkynyl C₈-C₂₄, substituted or unsubstituted aryl C₆-C₃₀,substituted or unsubstituted aralkyl C₇-C₂₄, substituted orunsubstituted heterocyclyl ring of 3-10 members, and substituted orunsubstituted heteroarylalkyl of 2 to 24 carbon atoms and 1 to 3 atomsother than carbon wherein the alkyl chain is of 1 to 6 carbon atoms and—NR₃R₄ is not an α-amino acid. Optionally, R₃ and R₄ can be bound by asaturated or unsaturated carbon-carbon bond, forming a cycle with thenitrogen atom. More preferably R₂ is —NR₃R₄ or —OR₃. More preferably, R₃and R₄ are independently selected from the group formed by H, a polymerderived from polyethylene glycol with a molecular weight comprisedbetween 200 and 35000 Daltons, methyl, ethyl, hexyl, dodecyl, orhexadecyl. Even more preferably R₃ and R₄ are independently selectedfrom the group formed by H, methyl, ethyl, hexyl, dodecyl, or hexadecyl.Even more preferably R₃ is H and R₄ is selected from the group formed byH, methyl, ethyl, hexyl, dodecyl, and hexadecyl. In accordance with aneven more preferred embodiment, R₂ is selected from —OH and —NH₂.

In accordance with another embodiment of this invention R₁ is selectedfrom the group formed by H, acetyl, lauroyl, myristoyl or palmitoyl,preferably R₁ is selected from the group formed by H, acetyl andpalmitoyl and R₂ is selected from the group formed by —OH and —NH₂.

In accordance with another particular embodiment the most preferredstructures of the polymer derived from polyethylene glycol are the group(—CH₂—CH₂—O)_(r)—H in which r is a number between 4 and 795 and thegroup

where s is a number between 1 and 125.

In accordance with another embodiment of this invention n, m, p and qare 0.

In accordance with another embodiment of this invention AA₁ is selectedfrom the group formed by -Arg-, -Lys-, -Gln-, -Asn-, -Glu- and -Asp-,AA₂ is selected from the group formed by -His-, -Gln-, -Asn-, -Glu- and-Asp-, AA₃ is selected from the group formed by -Leu- and -Phe-, AA₄ isselected from the group formed by -His-, -Lys-, -Gln- and -Leu-, AA₅ isselected from the group formed by -Arg-, -His-, -Lys-, -Gln-, -Asn-,-Glu- and -Asp-, AA₆ is selected from the group formed by -Trp- and-Val- and AA₇ is selected from the group formed by -Met-, -MetO— and-MetO₂. More preferably, AA₄ is selected from the group formed by -Lys-and -Leu-, and AA₆ is -Trp-. Even more preferably, n, m, p and q are 0.Additionally, the inventors of the present invention have found thatwhen AA₂ is selected from the group formed by -Asn- and -Glu-, theobtained compound is more chemically stable compared with other aminoacids in AA₂.

In accordance with another embodiment of this invention R₁ is selectedfrom the group formed by H, acetyl, lauroyl, myristoyl and palmitoyl,AA₁ is selected from the group formed by -L-Arg-, -L-Lys-, -L-Gln-,-L-Asn-, -L-Glu- and -L-Asp-, AA₂ is selected from the group formed by-L-His-, -L-Gln-, -L-Asn-, -L-Glu- and -L-Asp-, AA₃ is selected from thegroup formed by -L-Leu- and -L-Phe-, AA₄ is selected from the groupformed by -L-His-, -L-Lys-, -L-Gln- and -L-Leu-, AA₅ is selected fromthe group formed by -L-Arg-, -L-His-, -L-Lys-, -L-Gln-, -L-Asn-, -L-Glu-and -L-Asp-, AA₆ is selected from the group formed by -L-Trp- and-L-Val-, AA₇ is selected from the group formed by -L-Met-, -L-MetO— and-L-MetO₂—, and R₂ is selected from the group formed by —NR₃R₄ and —OR₃where R₃ and R₄ are independently selected from H, methyl, ethyl, hexyl,dodecyl and hexadecyl. More preferably, AA₄ is selected from the groupformed by -L-Lys- and -L-Leu-, and AA₆ is -L-Trp-. More preferably, R₁is acetyl or palmitoyl and R₂ is —NH₂. Even more preferably, n, m, p andq are 0.

In accordance with another embodiment of this invention R₁ is selectedfrom the group formed by H, acetyl, lauroyl, myristoyl and palmitoyl,AA₁ is selected from the group formed by -L-Asn-, -L-Glu- and -L-Asp-,AA₂ is selected from the group formed by -L-His- and -L-Asp-, AA₃ isselected from the group formed by -L-Leu- and -L-Phe-, AA₄ is selectedfrom the group formed by -L-Lys-, -L-Gln- and -L-Leu-, AA₅ is selectedfrom the group formed by -L-Arg-, -L-Gln-, -L-Asn- and -L-Asp-, AA₆ isselected from the group formed by -L-Trp-, AA₇ is selected from thegroup formed by -L-Met-, -L-MetO— and -L-MetO₂—, and R₂ is selected fromthe group formed by —NR₃R₄ and —OR₃ where R₃ and R₄ are independentlyselected from H, methyl, ethyl, hexyl, dodecyl and hexadecyl. Morepreferably, R₁ is acetyl or palmitoyl and R₂ is —NH₂. Even morepreferably, n, m, p and q are 0.

In accordance with another embodiment of this invention R₁ is selectedfrom the group formed by H, acetyl, lauroyl, myristoyl and palmitoyl,AA₁ is -L-Glu-, AA₂ is selected from the group formed by -L-Asn-,-L-Glu-, -L-Gln- and -L-Asp-, AA₃ is -L-Leu-, AA₄ is -L-Lys-, AA₅ is-L-Arg-, AA₆ is -L-Trp-, AA₇ is selected from the group formed by-L-Met-, -L-MetO— and -L-MetO₂—, and R₂ is selected from the groupformed by —NR₃R₄ and —OR₃ where R₃ and R₄ are independently selectedfrom H, methyl, ethyl, hexyl, dodecyl and hexadecyl. More preferably, R₁is acetyl or palmitoyl and R₂ is —NH₂. Even more preferably, n, m, p andq are 0.

In accordance with another embodiment of this invention R₁ is selectedfrom the group formed by H, acetyl, lauroyl, myristoyl or palmitoyl, AA₁is -L-Glu-, AA₂ is -L-His-, AA₃ is -L-Leu-, AA₄ is -L-Lys-, AA₅ is-L-Gln-, AA₆ is -L-Trp-, AA₇ is -L-Met-, -L-MetO— or -L-MetO₂— and R₂ is—NR₃R₄ or —OR₃ where R₃ and R₄ are independently selected from H,methyl, ethyl, hexyl, dodecyl and hexadecyl, preferably R₂ is —OH or—NH₂. More preferably, R₁ is acetyl or palmitoyl and R₂ is —NH₂. Evenmore preferably, n, m, p and q are 0.

In accordance with another embodiment of this invention R₁ is selectedfrom the group formed by H, acetyl, lauroyl, myristoyl or palmitoyl, AA₁is -L-Glu-, AA₂ is -L-Asp-, AA₃ is -L-Leu-, AA₄ is -L-Lys-, AA₅ is-L-Arg-, AA₆ is -L-Trp-, AA₇ is -L-Met-, -L-MetO— or -L-MetO₂— and R₂ is—NR₃R₄ or —OR₃ where R₃ and R₄ are independently selected from H,methyl, ethyl, hexyl, dodecyl and hexadecyl, preferably R₂ is —OH or—NH₂. More preferably, R₁ is acetyl or palmitoyl and R₂ is —NH₂. Evenmore preferably, n, m, p and q are 0.

In accordance with another embodiment of this invention R₁ is selectedfrom the group formed by H, acetyl, lauroyl, myristoyl or palmitoyl, AA₁is -L-Asn-, AA₂ is -L-His-, AA₃ is -L-Phe-, AA₄ is -L-Leu-, AA₅ is-L-Asn-, AA₆ is -L-Trp-, AA₇ is -L-Met-, -L-MetO— or -L-MetO₂— and R₂ is—NR₃R₄ or —OR₃ where R₃ and R₄ are independently selected from H,methyl, ethyl, hexyl, dodecyl and hexadecyl, preferably R₂ is —OH or—NH₂. More preferably, R₁ is acetyl or palmitoyl and R₂ is —NH₂. Evenmore preferably, n, m, p and q are 0.

In accordance with another embodiment of this invention R₁ is selectedfrom the group formed by H, acetyl, lauroyl, myristoyl or palmitoyl, AA₁is -L-Asp-, AA₂ is -L-His-, AA₃ is -L-Phe-, AA₄ is -L-Leu-, AA₅ is-L-Asp-, AA₆ is -L-Trp-, AA₇ is -L-Met-, -L-MetO— or -L-MetO₂— and R₂ is—NR₃R₄ or —OR₃ where R₃ and R₄ are independently selected from H,methyl, ethyl, hexyl, dodecyl and hexadecyl, preferably R₂ is —OH or—NH₂. More preferably, R₁ is acetyl or palmitoyl and R₂ is —NH₂. Evenmore preferably, n, m, p and q are 0.

In particular, the compounds in the invention which inhibit neuronalexocytosis, represented according to the formula (I) are selected fromthe group of peptide sequences outlined in Table 2, in which theirsequence identifier is detailed:

TABLE 2 SEQUENCE IDENTIFIER EHLKQWM SEQ ID NO: 1 QDFLHWM SEQ ID NO: 2QHLHNVM SEQ ID NO: 3 KDIKNWM SEQ ID NO: 4 DHLKQFM SEQ ID NO: 5 EHMKQYMSEQ ID NO: 6 KDLKEWM SEQ ID NO: 7 EHLKKWM SEQ ID NO: 8 DHLKEWMSEQ ID NO: 9 KDLRRWM SEQ ID NO: 10 DDLKRYM SEQ ID NO: 11 QHLKEWMSEQ ID NO: 12 RHFLQWM SEQ ID NO: 13 EDLKRWM SEQ ID NO: 14 NHFLNWMSEQ ID NO: 15 RHLKDWM SEQ ID NO: 16 DHFNQRM SEQ ID NO: 17 EDFQQHMSEQ ID NO: 18 EHFLEFM SEQ ID NO: 19 KHLQQIM SEQ ID NO: 20 NHFLKWMSEQ ID NO: 21 DHLKKWM SEQ ID NO: 22 NDLKDWM SEQ ID NO: 23 DHFQQRMSEQ ID NO: 24 DHFLDWM SEQ ID NO: 25 DHFLQWM SEQ ID NO: 26 QHLKNWMSEQ ID NO: 27 RDLIRKM SEQ ID NO: 28 NHFNNKM SEQ ID NO: 29 EHFLQWMSEQ ID NO: 30 NHLKNWM SEQ ID NO: 31 NHLKHWM SEQ ID NO: 32 QHFLRWMSEQ ID NO: 33 DHFLNWM SEQ ID NO: 34 EHLRQWM SEQ ID NO: 35 EHIKQWMSEQ ID NO: 36 EHMRQVM SEQ ID NO: 37 EHIMHWM SEQ ID NO: 38 DHMNRVMSEQ ID NO: 39 DDMKRWM SEQ ID NO: 40 NHYLNWM SEQ ID NO: 41 QHFINRMSEQ ID NO: 42 NHFVNYM SEQ ID NO: 43 QHFLNFM SEQ ID NO: 44 EHYQQRMSEQ ID NO: 45 RHLVQMM SEQ ID NO: 46 HHLIQMM SEQ ID NO: 47 HDIVRHMSEQ ID NO: 48 KHMMQIM SEQ ID NO: 49 Glu-His-Leu-Lys-Gln- SEQ ID NO: 50Trp-MetO Gln-Asp-Phe-Leu-His- SEQ ID NO: 51 Trp-MetOGln-His-Leu-His-Asn- SEQ ID NO: 52 Val-MetO Glu-Asp-Leu-Lys-Arg-SEQ ID NO: 53 Trp-MetO Asn-His-Phe-Leu-Asn- SEQ ID NO: 54 Trp-MetOAsp-His-Phe-Gln-Gln- SEQ ID NO: 55 Arg-MetO Asp-His-Phe-Leu-Asp-SEQ ID NO: 56 Trp-MetO Asp-His-Phe-Leu-Asn- SEQ ID NO: 57 Trp-MetOGlu-His-Leu-Lys-Gln- SEQ ID NO: 58 Trp-MetO₂ Glu-Asp-Leu-Lys-Arg-SEQ ID NO: 59 Trp-MetO₂ Asp-His-Phe-Gln-Gln- SEQ ID NO: 60 Arg-MetO₂Asp-His-Phe-Leu-Asp- SEQ ID NO: 61 Trp-MetO₂ EEHLKQWM SEQ ID NO: 62EHLKQWMR SEQ ID NO: 63 RQDFLHWM SEQ ID NO: 64 QDFLHWMH SEQ ID NO: 65DQHLHNVM SEQ ID NO: 66 QHLHNVMK SEQ ID NO: 67 EQHLKEWM SEQ ID NO: 68QHLKEWMR SEQ ID NO: 69 DEDLKRWM SEQ ID NO: 70 EDLKRWMK SEQ ID NO: 71ENHFLNWM SEQ ID NO: 72 NHFLNWMH SEQ ID NO: 73 DDHLKKWM SEQ ID NO: 74DHLKKWMR SEQ ID NO: 75 DDHFQQRM SEQ ID NO: 76 DHFQQRMR SEQ ID NO: 77EDHFLDWM SEQ ID NO: 78 DHFLDWMK SEQ ID NO: 79 ENHLKNWM SEQ ID NO: 80NHLKNWMH SEQ ID NO: 81 DDHFLNWM SEQ ID NO: 82 DHFLNWMR SEQ ID NO: 83Glu-His-Leu-Lys-Gln-Trp- SEQ ID NO: 84 MetO-Arg Asp-Glu-Asp-Leu-Lys-Arg-SEQ ID NO: 85 Trp-MetO Asn-His-Phe-Leu-Asn-Trp- SEQ ID NO: 86 MetO-ArgAsp-His-Phe-Gln-Gln-Arg- SEQ ID NO: 87 MetO-Arg Asp-His-Phe-Leu-Asp-Trp-SEQ ID NO: 88 MetO-Lys Glu-His-Leu-Lys-Gln-Trp- SEQ ID NO: 89 MetO₂-ArgAsp-Glu-Asp-Leu-Lys-Arg- SEQ ID NO: 90 Trp-MetO₂Asp-His-Phe-Gln-Gln-Arg- SEQ ID NO: 91 MetO₂-ArgAsp-His-Phe-Leu-Asp-Trp- SEQ ID NO: 92 MetO₂-Lys EEHLKQWMR SEQ ID NO: 93EHLKQWMRR SEQ ID NO: 94 DEQHLHNVM SEQ ID NO: 95 QHLHNVMRR SEQ ID NO: 96EEDLKRWMM SEQ ID NO: 97 DEEDLKRWM SEQ ID NO: 98 QRNHFLNWM SEQ ID NO: 99NHFLNWMMR SEQ ID NO: 100 EDHFQQRML SEQ ID NO: 101 DDHFQQRMRSEQ ID NO: 102 DHFLDWMRR SEQ ID NO: 103 DHDHFLDWM SEQ ID NO: 104EHFLQWMRM SEQ ID NO: 105 DEHFLQWMV SEQ ID NO: 106Glu-His-Leu-Lys-Gln-Trp-MetO- SEQ ID NO: 107 Arg-LysGln-Arg-Asn-His-Phe-Leu-Asn- SEQ ID NO: 108 Trp-MetOGlu-His-Leu-Lys-Gln-Trp-MetO₂- SEQ ID NO: 109 Arg-LysGln-Arg-Asn-His-Phe-Leu-Asn- SEQ ID NO: 110 Trp-MetO₂ EDVKRWMSEQ ID NO: 112 EQLKRWM SEQ ID NO: 113 DDVKKFM SEQ ID NO: 114 DNLKRFMSEQ ID NO: 115 EELKRWM SEQ ID NO: 116 ENLKRWM SEQ ID NO: 117 EDVRRWMSEQ ID NO: 118 EHFLEWM SEQ ID NO: 119 DEIHKWM SEQ ID NO: 120 ENLRRWMSEQ ID NO: 121 DNLHKYM SEQ ID NO: 122 EQIKHFM SEQ ID NO: 123 DNMRRFMSEQ ID NO: 124 EEMKRWM SEQ ID NO: 125 DQMKHYM SEQ ID NO: 126Glu-Glu-Leu-Lys-Arg-Trp-MetO SEQ ID NO: 127 Asp-Asp-Val-His-Arg-Trp-MetOSEQ ID NO: 128 Glu-Asn-Leu-Lys-Arg-Trp-MetO SEQ ID NO: 129Asp-Glu-Val-Arg-His-Tyr-MetO SEQ ID NO: 130Glu-Glu-Leu-Lys-Arg-Trp-MetO₂ SEQ ID NO: 131Glu-Asn-Leu-Lys-Arg-Trp-MetO₂ SEQ ID NO: 132Asp-Gln-Ile-Arg-Lys-Phe-MetO₂ SEQ ID NO: 133 EEQLKRWM SEQ ID NO: 134EQLKRWMR SEQ ID NO: 135 REELKRWM SEQ ID NO: 136 EELKRWMH SEQ ID NO: 137DENLKRWM SEQ ID NO: 138 ENLKRWMK SEQ ID NO: 139 EDNLKRFM SEQ ID NO: 140DNLKRFMR SEQ ID NO: 141 EEQIKHFM SEQ ID NO: 142 EQIKHFMH SEQ ID NO: 143Glu-Glu-Leu-Lys-Arg-Trp-MetO-Arg SEQ ID NO: 144Glu-Asn-Leu-Lys-Arg-Trp-MetO-Arg SEQ ID NO: 145Glu-Glu-Leu-Lys-Arg-Trp-MetO₂-Arg SEQ ID NO: 146Glu-Asn-Leu-Lys-Arg-Trp-MetO₂-Arg SEQ ID NO: 147 EEQLKRWMRSEQ ID NO: 148 EQLKRWMRR SEQ ID NO: 149 DEELKRWMR SEQ ID NO: 150EELKRWMRR SEQ ID NO: 151 QRENLKRWM SEQ ID NO: 152 ENLKRWMMRSEQ ID NO: 153 QREQIKHFM SEQ ID NO: 154 EQIKHFMMR SEQ ID NO: 155Glu-Glu-Leu-Lys-Arg-Trp-MetO- SEQ ID NO: 156 Arg-LysGln-Arg-Glu-Asn-Leu-Lys-Arg- SEQ ID NO: 157 Trp-MetOGlu-Asn-Leu-Lys-Arg-Trp-MetO₂- SEQ ID NO: 158 Arg-LysGln-Arg-Glu-Glu-Leu-Lys-Arg- SEQ ID NO: 159 Trp-MetO₂

their stereoisomers, mixtures thereof and/or their cosmetically orpharmaceutically acceptable salts.

The compounds of this invention can exist as stereoisomers or mixturesof stereoisomers; for example, the amino acids which comprise them canhave the configuration L-, D-, or be racemic independently of eachother. Therefore, it is possible to obtain isomeric mixtures as well asracemic mixtures or diastereomeric mixtures, or pure diastereomers orenantiomers, depending on the number of asymmetric carbons and on whichisomers or isomeric mixtures are present. The preferred structures ofthe compounds of the invention are pure isomers, i.e., enantiomers ordiastereomers.

For example, when it is stated that AA₁ can be -Lys-, it is understoodthat AA₁ is selected from -L-Lys-, -D-Lys- or mixtures of both, racemicor non-racemic. The preparation procedures described in this documentenable the person skilled in the art to obtain each of the stereoisomersof the compound of the invention by choosing the amino acid with theright configuration.

In the context of this invention, the term “amino acids” includes theamino acids encoded by the genetic code as well as non-encoded aminoacids, whether they are natural or not. Examples of non-encoded aminoacids are, without restriction, citrulline, ornithine, sarcosine,desmosine, norvaline, 4-aminobutyric acid, 2-aminobutyric acid,2-aminoisobutyric acid, 6-aminohexanoic acid, 1-naphthylalanine,2-naphthylalanine, 2-aminobenzoic acid, 4-aminobenzoic acid,4-chlorophenylalanine, 2,3-diaminopropionic acid, 2,4 diaminobutyricacid, cycloserine, carnitine, cystine, penicillamine, pyroglutamic acid,thienylalanine, hydroxyproline, allo-isoleucine, allo-threonine,isonipecotic acid, isoserine, phenylglycine, statin, β-alanine,norleucine, N-methyl amino acids, α-amino acids and β-amino acids, amongothers, as well as their derivatives. A list of non-natural amino acidscan be found in the article “Unusual amino acids in peptide synthesis”by D. C. Roberts and F. Vellaccio, in The Peptides, Vol. 5 (1983),Chapter VI, Gross E. and Meienhofer J., Eds., Academic Press, New York,USA or in the commercial catalogs of the companies specialized in thefield.

In the context of this invention, when n, m, p or q are not 0 it isclearly understood that the nature of W, X, Y and/or Z does not hinderthe activity of the compounds of the invention, but that it contributesto the inhibition of neuronal exocytosis or has no effect on it.

The cosmetically and pharmaceutically acceptable salts of the peptidesprovided by this invention are also found within the field of thisinvention. The term “cosmetically or pharmaceutically acceptable salts”means a salt recognized for its use in animals and more specifically inhuman beings, and includes salts used to form base addition salts,either they are inorganic, such as and not restricted to, lithium,sodium, potassium, calcium, magnesium, manganese, copper, zinc oraluminum among others, either they are organic, such as and notrestricted to, ethylamine, diethylamine, ethylenediamine, ethanolamine,diethanolamine, arginine, lysine, histidine or piperazine among others,or acid addition salts, either they are organic, such as and notrestricted to, acetate, citrate, lactate, malonate, maleate, tartrate,fumarate, benzoate, aspartate, glutamate, succinate, oleate,trifluoroacetate, oxalate, pamoate or gluconate among others, orinorganic, such as and not restricted to, chloride, sulfate, borate orcarbonate, among others. The nature of the salt is not critical,provided that it is cosmetically or pharmaceutically acceptable. Thecosmetically or pharmaceutically acceptable salts of the peptides of theinvention can be obtained by the conventional methods, well known in theprior art [Berge S. M. et al., “Pharmaceutical Salts”, (1977), J. Pharm.Sci., 66, 119].

Preparation Procedures of the Compounds of the Invention

Synthesis of the compounds of the invention, their stereoisomers,mixtures thereof and/or their cosmetically or pharmaceuticallyacceptable salts can be carried out according to conventional methods,known in the prior art, such as using solid phase peptide synthesismethods [Stewart J. M. and Young J. D., “Solid Phase Peptide Synthesis,2nd edition”, (1984), Pierce Chemical Company, Rockford, Ill.; BodanzskyM. and Bodanzsky A., “The practice of Peptide Synthesis”, (1994),Springer Verlag, Berlin; Lloyd-Williams P. et al., “Chemical Approachesto the Synthesis of Peptides and Proteins”, (1997), CRC, Boca Raton,Fla., USA], synthesis in solution, enzymatic synthesis [Kullmann W“Proteases as catalysts for enzymic syntheses of opioid peptides”,(1980), J. Biol. Chem., 255(17), 82348238] or any combination thereof.Compounds can also be obtained by fermentation of a strain of bacteria,modified or unmodified, by genetic engineering with the objective ofproducing the desired sequences, or by controlled hydrolysis of proteinswith animal, fungal, or preferably plant origins, which free peptidefragments which contain, at least, the desired sequence.

For example, a method of obtaining the compounds (I) of the invention,their stereoisomers and mixtures thereof comprises the stages of:

-   -   coupling of an amino acid, with the N-terminal end protected and        the C-terminal end free, with an amino acid with the N-terminal        end free and the C-terminal end protected or bound to a solid        support;    -   elimination of the group protecting the N-terminal end;    -   repetition of the coupling sequence and elimination of the group        protecting the N-terminal end until the desired peptide sequence        is obtained;    -   elimination of the group protecting the C-terminal end or        cleavage of the solid support.

Preferably, the C-terminal end is bound to a solid support and theprocedure is carried out in solid phase and, therefore, comprises thecoupling of an amino acid with the protected N-terminal end and the freeC-terminal end with an amino acid with the N-terminal end free and theC-terminal end bound to a polymeric support; elimination of the groupprotecting the N-terminal end; and repetition of this sequence as manytimes as is necessary to thus obtain the compound of the desired length,finally followed by the cleavage of the synthesized compound from theoriginal polymeric support.

The functional groups of the side chains of the amino acids aremaintained conveniently protected with temporary or permanent protectivegroups throughout synthesis, and can be unprotected simultaneously ororthogonally to the process of cleavage of the peptide from thepolymeric support.

Alternatively, solid phase synthesis can be carried out using aconvergent strategy coupling a peptide with the polymeric support orwith a peptide or amino acid previously bound to the polymeric support.Convergent synthesis strategies are widely known by persons skilled inthe art and are described in Lloyd-Williams P. et al., “ConvergentSolid-Phase Peptide Synthesis”, (1993), Tetrahedron, 49(48),11065-11133.

The procedure can comprise the additional stages of deprotection of theN-terminal and C-terminal ends and/or cleavage of the peptide from thepolymeric support in an indiscriminate order, using standard proceduresand conditions known in the prior art, after which the functional groupsof these ends can be modified. The optional modification of theN-terminal and C-terminal ends can be carried out with the peptide offormula (I) anchored to the polymeric support or once the peptide hasbeen separated from the polymeric support.

Optionally, R₁ can be introduced by the reaction of the N-terminal endof the compound of the invention with a R₁—X compound, wherein R₁ hasthe aforementioned meaning and X is a leaving group, such as and notrestricted to, the tosyl group, the mesyl group and halogen groups amongothers; through a nucleophilic substitution reaction, in the presence ofan adequate base and solvent, wherein the fragments that have thefunctional groups not involved in the N—C bond formation are suitablyprotected with temporary or permanent protective groups.

Optionally and/or additionally, the R₂ radicals can be introduced by thereaction of a compound HR₂ wherein R₂ is —OR₃, —NR₃R₄ or —SR₃, with acomplementary fragment which corresponds to the compound of formula (I)in which R₂ is —OH in the presence of an adequate solvent and a basesuch as, N,N-diisopropylethylamine (DIEA) or triethylamine or anadditive such as 1-hydroxybenzotriazole (HOBt) or1-hydroxyazabenzotriazole (HOAt) and a dehydrating agent, such as acarbodiimide, a uronium salt, a phosphonium salt or amidinium salt,among others, or by prior formation of an acyl halide with, for example,thionyl chloride, and thereby obtaining a peptide according to theinvention of general formula (I), wherein the fragments that have thefunctional groups not involved in the N—C bond formation are suitablyprotected with temporary or permanent protective groups, oralternatively other R₂ radicals may be introduced by simultaneousincorporation to the cleavage process of the peptide from the polymericsupport.

A person skilled in the art would easily understand that thedeprotection/cleavage steps of the C-terminal and N-terminal ends andtheir subsequent derivatization can be performed in a different order,according to the processes known in the prior art.

The term “protective group” relates to a group which blocks an organicfunctional group and which can be removed in controlled conditions. Theprotective groups, their relative reactivities and the conditions inwhich they remain inert are known to the person skilled in the art.

Examples of representative protective groups for the amino group areamides, such as amide acetate, amide benzoate, amide pivalate;carbamates such as benzyloxycarbonyl (Cbz or Z), 2-chlorobenzyl (CIZ),para-nitrobenzyloxycarbonyl (pNZ), tert-butyloxycarbonyl (Boc),2,2,2-trichloroethyloxycarbonyl (Troc),2-(trimethylsilyl)ethyloxycarbonyl (Teoc), 9-fluorenylmethyloxycarbonyl(Fmoc) or allyloxycarbonyl (Alloc), Trityl (Trt), methoxytrityl (Mtt),2,4-dinitrophenyl (Dnp),N-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl (Dde),1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl (ivDde),1-(1-adamantyl)-1-methylethoxycarbonyl (Adpoc), among others, preferablyBoc or Fmoc.

Examples of representative protective groups for the carboxyl group areesters, such as the tert-butyl ester (tBu), allyl ester (All),triphenylmethyl ester (Trt ester), cyclohexyl ester (cHx), benzyl ester(Bzl), ortho-nitrobenzyl ester, para-nitrobenzyl ester,para-methoxybenzyl ester, trimethylsilylethyl ester, 2-phenylisopropylester, fluorenylmethyl ester (Fm),4-(N41-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]amino)benzylester (Dmab), among others; preferred protective groups of the inventionare the All, tBu, cHx, Bzl and Trt esters.

The side chains of the trifunctional amino acids can be protected duringthe synthetic process with temporary or permanent protective groupsorthogonal to the protective groups of the N-terminal and C-terminalends.

The hydroxyl group of the tyrosine side chain can be protected with the2-bromobenzyloxycarbonyl group (2-BrZ), tBu, All, Bzl or2,6-dichlorobenzyl (2,6-diCIZ) among others. The histidine side chaincan be protected by a protective group selected from the group formed byTos, Dnp, methyl (Me), Boc, benzyloxymethyl (Bom), Bzl, Fmoc, Mts, Trtand Mtt. The amide group of the glutamine and asparagine side chain canbe protected by the Trt group or xanthyl group (Xan) or can be usedunprotected. For the protection of the carboxyl group of the asparticacid and glutamic acid side chain esters can be used such as tBu ester,All ester, triphenylmethyl ester (Trt ester), cHx ester, Bzl ester,orto-nitrobenzyl ester, para-nitrobenzyl ester, para-methoxybenzylester, trimethylsilylethyl ester, 2-phenylisopropyl ester, Fm ester orDmab ester, among others. The arginine side chain can be protected by aprotective group selected from the group formed by Tos,4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), Alloc, nitro,2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf) and2,2,5,7,8-pentamethylchroman-6-sulfonyl (Pmc). The indole group of thetryptophan side chain can be protected by the formyl group (For), Boc,Mts or can be used unprotected. For the protection of the amino groupsof the lysine side chains amides can be used, such as amide acetate,amide benzoate, amide pivalate; carbamates such as Cbz or Z, CIZ, pNZ,Boc, Troc, Teoc, Fmoc or Alloc, Trt, Mtt, Dnp, Dde, ivDde, Adpoc, amongothers. The methionine side chain can be protected in sulfoxide form, insulfone form or used without protection. The methionyl(sulfoxide) andmethionyl(sulfone) side chains are not protected.

In a preferred embodiment, the protective group strategy used is thestrategy wherein the amino groups are protected by Boc, the carboxylgroups are protected by Bzl, cHx or All, the tyrosine side chain isprotected with 2-BrZ or Bzl, the histidine side chain is protected bythe Tos or Bom group, the aspartic acid and glutamic acid side chainsare protected with Bzl, cHx or All, glutamine and asparagine are usedwithout protection in their side chain, methionine is used withoutprotection in its side chain, the arginine side chain is protected byTos, the tryptophan side chain is protected by For or Mts and the lysineside chain is protected by CIZ, Fmoc or Alloc.

In another preferred embodiment, the protective group strategy used isthe strategy wherein the amino groups are protected by Fmoc, thecarboxyl groups are protected by the tBu, All or Trt esters, thetyrosine side chain is protected by tBu, the histidine side chain isprotected by the Trt or Mtt group, the aspartic acid and glutamic acidside chains are protected with tBu or All, glutamine and asparagine areprotected by the Trt group in their side chain, methionine is usedwithout protection in its side chain, the arginine side chain isprotected by Pmc or Pbf, the tryptophan side chain is protected by Bocor is used unprotected, and the lysine side chain is protected by Boc,Trt or Alloc.

Examples of these and other additional protective groups, theirintroduction and removal, can be found in the literature [Atherton B.and Sheppard R. C., “Solid Phase Peptide Synthesis: A practicalapproach”, (1989), IRL Oxford University Press]. The term “protectivegroups” also includes the polymeric supports used in solid phasesynthesis.

When synthesis takes place totally or partially in solid phase, thepossible solid supports used in the procedure of the invention involvepolystyrene supports, polyethylene glycol grafted to polystyrene andsimilar, such as and not restricted to, p-methylbenzhydrylamine resins(MBHA) [Matsueda G. R. et al., “A p-methylbenzhydrylamine resin forimproved solid phase synthesis of peptide amides”, (1981), Peptides, 2,4550], 2-chlorotrityl resins [Barlos K. et al., “Darstellung geschützterPeptidFragmente unter Einsatz substituierter TriphenylmethylHarze”,(1989), Tetrahedron Lett., 30, 39433946; Barlos K. et al., “Veresterungvon partiell geschützten PeptidFragmenten mit Harzen. Einsatz von2-Chlorotritylchlorid zur Synthese von Leu1Gastrin I”, (1989),Tetrahedron Lett., 30, 39473951], TentaGel® resins (Rapp Polymere GmbH),ChemMatrix® resins (Matrix Innovation, Inc.) and similar, which may ormay not include a labile linker, such as5-(4-aminomethyl-3,5-dimethoxyphenoxy) valeric acid (PAL) [Albericio F.et al., “Preparation and application of the5-(4-(9-fluorenylmethyloxycarbonyl)aminomethyl-3,5-dimethoxy-phenoxy)valeric acid (PAL) handle for thesolid phase synthesis of C-terminal peptide amides under mildconditions”; (1990), J. Org. Chem., 55, 37303743],2-[4-aminomethyl-(2,4-dimethoxyphenyl)]phenoxyacetic acid (AM) [Rink H.,“Solid phase synthesis of protected peptide fragments using atrialkoxy-diphenyl-methylester resin”, (1987), Tetrahedron Lett., 28,3787-3790], Wang [Wang S. S., “p-Alkoxybenzyl Alcohol Resin andp-Alkoxybenzyloxycarbonylhydrazide Resin for Solid Phase Synthesis ofProtected Peptide Fragments”, (1973), J. Am. Chem. Soc., 95, 1328-1333]and similar, which enable simultaneous deprotection and cleavage of thepeptide from the polymeric support.

Cosmetic or Pharmaceutical Compositions of the Invention

The compounds of the invention can be administered to inhibit neuronalexocytosis by any means which causes contact between the compounds andthe site of action in a mammal's body, preferably that of a human being,and in the form of a composition which contains them.

To this regard, another aspect of the invention is a cosmetic orpharmaceutical composition which comprises at least one compound ofgeneral formula (I), its stereoisomers, mixtures thereof, and/or itscosmetically or pharmaceutically acceptable salts together with at leastone cosmetically or pharmaceutically acceptable adjuvant. Thesecompositions can be prepared by conventional means known to personsskilled in the art [“Harry's Cosmeticology”, Seventh edition, (1982),Wilkinson J. B., Moore R. J., ed. Longman House, Essex, GB].

The compounds of this invention have variable solubility in water,according to the nature of their amino acid sequence or any possiblemodifications in the N-terminal and/or C-terminal ends. Therefore, thecompounds of this invention can be incorporated into the compositions byaqueous solution, and those which are not soluble in water can besolubilized in cosmetically or pharmaceutically acceptable conventionalsolvents such as and not restricted to, ethanol, propanol, isopropanol,propylene glycol, glycerin, butylene glycol or polyethylene glycol orany combination thereof.

The cosmetically or pharmaceutically effective amount of the compoundsof the invention which should be administered, as well as their dosage,will depend on numerous factors, including age, state of the patient,the nature or severity of the condition, disorder or disease to betreated and/or cared for, the route and frequency of administration andthe particular nature of the compounds to be used.

“Cosmetically and pharmaceutically effective amount” is understood tomean a non-toxic but sufficient amount of the compound or compounds ofthe invention to provide the desired effect. The compounds of theinvention are used in the cosmetic or pharmaceutical composition of thisinvention at cosmetically or pharmaceutically effective concentrationsto achieve the desired effect; in a preferred form with regards to thetotal weight of the composition, between 0.00000001% (in weight) and 20%(in weight); preferably between 0.000001% (in weight) and 15% (inweight), more preferably between 0.0001% (in weight) and 10% (in weight)and even more preferably between 0.0001% (in weight) and 5% (in weight).

The compounds of general formula (I), their stereoisomers, mixturesthereof and/or their cosmetic or pharmaceutically acceptable salts, canalso be incorporated into cosmetic or pharmaceutical delivery systemsand/or sustained release systems.

The term “delivery systems” relates to a diluent, adjuvant, excipient orcarrier with which the compound of the invention is administered. Thesecosmetic or pharmaceutical carriers can be liquids, such as water, oilsor surfactants, including those of petroleum, animal, plant or syntheticorigin, such as and not restricted to, peanut oil, soybean oil, mineraloil, sesame oil, castor oil, polysorbates, sorbitan esters, ethersulfates, sulfates, betaines, glycosides, maltosides, fatty alcohols,nonoxynols, poloxamers, polyoxyethylenes, polyethylene glycols,dextrose, glycerol, digitonin and similar. A person skilled in the artknows the diluents, adjuvants or excipients which can be used in thedifferent delivery systems in which the compound of the invention can beadministered.

The term “sustained release” is used in a conventional sense relating toa delivery system of a compound which provides the gradual release ofthis compound during a period of time and preferably, although notnecessarily, with relatively constant compound release levels over along period of time.

Examples of delivery or sustained release systems include, withoutrestriction, liposomes, mixed liposomes, oleosomes, niosomes, ethosomes,milliparticles, microparticles, nanoparticles and solid lipidnanoparticles, nanostructured lipid carriers, sponges, cyclodextrins,vesicles, micelles, mixed micelles of surfactants,surfactant-phospholipid mixed micelles, millispheres, microspheres andnanospheres, lipospheres, millicapsules, microcapsules and nanocapsules,as well as in microemulsions and nanoemulsions, which can be added toachieve a greater penetration of the active principle and/or improve itspharmacokinetic and pharmacodynamic properties. Preferred delivery orsustained release systems are liposomes, surfactant-phospholipid mixedmicelles, microemulsions, more preferably water-in-oil microemulsionswith an internal structure of reverse micelle and nanocapsulescontaining microemulsions.

The sustained release systems can be prepared by methods known in theprior art, and the compositions which contain them can be administered,for example, by topical or transdermal administration, includingadhesive patches, non-adhesive patches, occlusive patches andmicroelectric patches, or by systemic administration, for example andnot restricted to, oral or parenteral route, including nasal, rectal orsubcutaneous implantation or injection, or direct implantation orinjection into a specific body part, and preferably should release arelatively constant quantity of the peptides of the invention. Theamount of compound contained in the sustained release system willdepend, for example, on where the composition is to be administered, thekinetics and duration of the release of the compound of the invention,as well as the nature of the condition, disorder and/or disease to betreated and/or cared for.

The compounds of this invention can also be adsorbed on solid organicpolymers or solid mineral supports such as and not restricted to, talc,bentonite, silica, starch or maltodextrin among others.

The compositions which contain the compounds of general formula (I),their stereoisomers, mixtures thereof and/or their cosmetically orpharmaceutically acceptable salts can also be incorporated into fabrics,non-woven fabrics and medical devices which are in direct contact withthe skin, thus releasing the compounds of the invention whether bybiodegradation of the binding system to the fabric, non-woven fabric ormedical device, or by friction between them and the body, due to bodilymoisture, the skin's pH or body temperature. Furthermore, the compoundsof the invention can be incorporated into the fabrics and non-wovenfabrics used to make garments that are in direct contact with the body.Preferably, the fabrics, non-woven fabrics and medical devicescontaining the compounds of the invention are used for the treatmentand/or care of conditions, disorders and/or diseases which improve orare prevented, delayed or hindered by the inhibition of neuronalexocytosis.

Examples of fabrics, non-woven fabrics, garments, medical devices andmeans for immobilizing the compounds to them, among which are thedelivery systems and/or the sustained release systems described above,can be found in the literature and are known in the prior art [Schaab C.K. (1986) HAPPI May 1986; Nelson G., “Application of microencapsulationin textiles”, (2002), Int. J. Pharm., 242(1-2), 55-62; “BiofunctionalTextiles and the Skin” (2006) Curr. Probl. Dermatol. v.33, Hipler U. C.and Elsner P., eds. S. Karger A G, Basel, Switzerland; Malcolm R. K. etal., “Controlled release of a model antibacterial drug from a novelself-lubricating silicone biomaterial”, (2004), J. Cont. Release, 97(2),313-320]. The preferred fabrics, non-woven fabrics, garments and medicaldevices are bandages, gauzes, t-shirts, socks, tights, underwear,girdles, gloves, diapers, sanitary napkins, dressings, bedspreads,wipes, adhesive patches, non-adhesive patches, occlusive patches,microelectric patches and/or face masks.

The cosmetic or pharmaceutical compositions which contain the compoundsof the invention, their stereoisomers, mixtures thereof and/or theircosmetically or pharmaceutically acceptable salts, can be used indifferent types of compositions of topical or transdermal applicationwhich optionally include cosmetically or pharmaceutically acceptableexcipients necessary for formulating the desired administration form. Aperson skilled in the art knows the different excipients which can beused in the cosmetic or pharmaceutical compositions which contain thecompounds of the invention.

The compositions of topical or transdermal application can be producedin any solid, liquid or semi-solid formulation, such as and notrestricted to, creams, multiple emulsions such as and not restricted to,oil and/or silicone in water emulsions, water-in-oil and/or siliconeemulsions, water/oil/water or water/silicone/water type emulsions, andoil/water/oil or silicone/water/silicone type emulsions, anhydrouscompositions, aqueous dispersions, oils, milks, balsams, foams, lotions,gels, cream gels, hydroalcoholic solutions, hydroglycolic solutions,hydrogels, liniments, sera, soaps, shampoos, conditioners, serums,polysaccharide films, ointments, mousses, pomades, powders, bars,pencils and sprays or aerosols (sprays), including leave-on andrinse-off formulations. These topical or transdermal applicationformulations can be incorporated using techniques known by the personskilled in the art into different types of solid accessories such as andnot restricted to, bandages, gauzes, t-shirts, socks, tights, underwear,girdles, gloves, diapers, sanitary napkins, dressings, bedspreads,wipes, adhesive patches, non-adhesive patches, occlusive patches,microelectric patches or face masks, or they can be incorporated intodifferent make-up products such as make-up foundation, such as fluidfoundations and compact foundations, make-up removal lotions, make-upremoval milks, under-eye concealers, eye shadows, lipsticks, lipprotectors, lip gloss and powders, among others.

The cosmetic or pharmaceutical compositions of the invention may includeagents which increase the percutaneous absorption of the compounds ofthis invention, such as and not restricted to, dimethyl sulfoxide,dimethylacetamide, dimethylformamide, surfactants, azone(1-dodecylazacycloheptane-2-one), alcohol, urea, ethoxydiglycol,acetone, propylene glycol or polyethylene glycol, among others.Furthermore, the cosmetic or pharmaceutical compositions of thisinvention can be applied to local areas to be treated by means ofiontophoresis, sonophoresis, electroporation, microelectric patches,mechanical pressure, osmotic pressure gradient, occlusive cure,microinjections or needle-free injections by means of pressure, such asinjections by oxygen pressure, or any combination thereof, to achieve agreater penetration of the compound of the invention. The applicationarea will be determined by the nature of the condition, disorder and/ordisease to be treated and/or cared for.

Furthermore, the cosmetic compositions containing the compounds ofgeneral formula (I), their stereoisomers, mixtures thereof and/or theircosmetically or pharmaceutically acceptable salts can be used indifferent types of formulations for oral administration, preferably inthe form of oral cosmetics or drugs, such as and not restricted to,capsules, including gelatin capsules, soft capsules, hard capsules,tablets, including sugar coated tablets, pills, powders, granules,chewing gum, solutions, suspensions, emulsions, syrups, elixirs,polysaccharide films, jellies or gelatins, and any other form known bythe person skilled in the art. In a particular embodiment, the compoundsof the invention can be incorporated into any form of functional food orfortified food, such as and not restricted to, dietary bars or compactor non-compact powders. These powders can be dissolved in water, soda,dairy products, soy derivatives or can be incorporated into dietarybars. The compounds of this invention can be formulated with commonexcipients and adjuvants for oral compositions or food supplements, suchas and not restricted to, fat components, aqueous components,humectants, preservatives, texturizing agents, flavors, aromas,antioxidants and colorants common in the food industry.

Cosmetic or pharmaceutical compositions containing the compounds ofgeneral formula (I), their stereoisomers, mixtures thereof and/or theircosmetically or pharmaceutically acceptable salts can also beadministered, as well as by topical or transdermal route, by any otherappropriate route, such as oral or parenteral route, for which they willinclude the pharmaceutically acceptable excipients necessary for theformulation of the desired administration form. In the context of thisinvention, the term “parenteral” includes nasal, auricular, ophthalmic,rectal, urethral, vaginal, subcutaneous, intradermal, intravascularinjections such as intravenous, intramuscular, intraocular,intravitreous, intracorneal, intraspinal, intramedullary, intracranial,intracervical, intracerebral, intrameningeal, intraarticular,intrahepatic, intrathoracic, intratracheal, intrathecal andintraperitoneal, and any another similar injection or infusiontechnique. A person skilled in the art knows the different means bywhich the cosmetic or pharmaceutical compositions which contain thecompounds of the invention can be administered.

Among the cosmetically or pharmaceutically acceptable excipients and/oradjuvants contained in the cosmetic or pharmaceutical compositionsdescribed in this invention are additional ingredients commonly used incosmetic or pharmaceutical compositions, such as and not restricted to,other agents which inhibit neuronal exocytosis, other anticholinergicagents, other agents which inhibit muscular contraction, otheranti-aging agents, other anti-wrinkle agents, other antiperspirantagents, other anti-inflammatory agents and/or analgesics, otheranti-itching agents, calming agents, anesthetic agents, inhibitors ofacetylcholine-receptor aggregation, agents that inhibitacetylcholinesterase, skin relaxant agents, melanin synthesisstimulating or inhibiting agents, whitening or depigmenting agents,propigmenting agents, self-tanning agents, NO-synthase inhibitingagents, 5α-reductase inhibiting agents, lysyl- and/or prolyl hydroxylaseinhibiting agents, antioxidants, free radical scavengers and/or agentsagainst atmospheric pollution, reactive carbonyl species scavengers,anti-glycation agents, antihistamine agents, antiviral agents,antiparasitic agents, emulsifiers, emollients, organic solvents, liquidpropellants, skin conditioners, humectants, substances that retainmoisture, alpha hydroxy acids, beta hydroxy acids, moisturizers,epidermal hydrolytic enzymes, vitamins, amino acids, proteins, pigmentsor colorants, dyes, biopolymers, gelling polymers, thickeners,surfactants, softening agents, emulsifiers, binding agents,preservatives, agents able to reduce or treat the bags under the eyes,exfoliating agents, keratolytic agents, flaking agents, antimicrobialagents, antifungal agents, fungistatic agents, bactericidal agents,bacteriostatic agents, agents stimulating the synthesis of dermal orepidermal macromolecules and/or capable of inhibiting or preventingtheir degradation, collagen synthesis-stimulating agents, elastinsynthesis-stimulation agents, decorin synthesis-stimulation agents,laminin synthesis-stimulation agents, defensin synthesis-stimulatingagents, chaperone synthesis-stimulating agents, cAMPsynthesis-stimulating agents, AQP-3 modulating agents, aquaporinsynthesis modulating agents, proteins from the aquaporin family,hyaluronic acid synthesis-stimulating agents, glycosaminoglycansynthesis-stimulating agents, fibronectin synthesis-stimulating agents,sirtuin synthesis-stimulating agents, sirtuin activating agents, heatshock proteins, heat shock protein synthesis-stimulating agents, agentsstimulating the synthesis of lipids and components of the stratumcorneum, ceramides, fatty acids, agents that inhibit collagendegradation, matrix metalloproteinase inhibitory agents, agents thatinhibit elastin degradation, agents that inhibit serine proteases suchas kallikreins, leukocyte elastase or cathepsin G, agents stimulatingfibroblast proliferation, agents stimulating keratinocyte proliferation,agents stimulating adipocyte proliferation, agents stimulatingmelanocyte proliferation, agents stimulating keratinocytedifferentiation, agents stimulating or delaying adipocytedifferentiation, antihyperkeratosis agents, comedolytic agents,anti-psoriasis agents, DNA repair agents, DNA protecting agents,stabilizers, agents for the treatment and/or care of sensitive skin,firming agents, anti-stretch mark agents, binding agents, agentsregulating sebum production, lipolytic agents or agents stimulatinglipolysis, adipogenic agents, agents modulating PGC-1α expression,agents modulating the activity of PPARγ, agents which increase or reducethe triglyceride content of adipocytes, anti-cellulite agents, agentswhich inhibit the activity of PAR-2, agents stimulating healing,coadjuvant healing agents, agents stimulating reepithelialization,coadjuvant reepithelialization agents, cytokine growth factors, agentsacting on capillary circulation and/or microcirculation, agentsstimulating angiogenesis, agents that inhibit vascular permeability,venotonic agents, agents acting on cell metabolism, agents to improvedermal-epidermal junction, agents inducing hair growth, hair growthinhibiting or retardant agents, hair loss retardant agents,preservatives, perfumes, cosmetic and/or absorbent and/or body odormasking deodorants, chelating agents, plant extracts, essential oils,marine extracts, agents obtained from a biotechnological process,mineral salts, cell extracts, sunscreens and organic or mineralphotoprotective agents active against ultraviolet A and/or B rays and/orinfrared A rays, or mixtures thereof, provided that they are physicallyand chemically compatible with the rest of components in the compositionand particularly with the compounds of the invention. Likewise, thenature of these additional ingredients should not unacceptably alter thebenefits of the compounds of this invention. The nature of theseadditional ingredients can be synthetic or natural, such as plantextracts, or come from a biotechnological procedure, or from acombination of a synthetic procedure and a biotechnological procedure.Additional examples can be found in CTFA International CosmeticIngredient Dictionary & Handbook, 12th Edition (2008). In the context ofthis invention, biotechnological procedure is understood to be anyprocedure to produce the active ingredient, or part of it, in anorganism, or in part of it.

An additional aspect of this invention refers to a cosmetic orpharmaceutical composition which comprises a cosmetically orpharmaceutically effective quantity of at least one compound generalformula (I), its stereoisomers, mixtures thereof and/or its cosmeticallyor pharmaceutically acceptable salts, as well as a cosmetically orpharmaceutically effective quantity of at least one extract, syntheticcompound or product of biotechnological origin which is an anti-wrinkleagent and/or anti-aging agent such as and not restricted to the extractsor hydrolyzed extracts of Vitis vinifera, Rosa canina, Curcuma longa,Theobroma cacao, Ginkgo biloba, Leontopodium alpinum or Dunaliellasalina among others, Matrixyl® [INCI: Palmitoyl Pentapeptide-4],Matrixyl® 3000° [INCI: Palmitoyl Tetrapeptide-7, PalmitoylOligopeptide], Matrixyl® Synthe'6™ [INCI: Glycerin, Water, HydroxypropylCyclodextrin, Palmitoyl Tripeptide-38], Essenskin™ [INCI: calciumhydroxymethionine], Renovage [INCI: teprenone], Resistem™ [INCI:Globularia Cordifolia Ferment] or Dermaxyl® [INCI: PalmitoylOligopeptide] marketed by Sederma/Croda, Vialox® [INCI: Pentapeptide-3],Syn® Ake® [INCI: Dipeptide Diaminobutyroyl Benzylamide Diacetate],Syn®-Coll [INCI: Palmitoyl Tripeptide-5], Phytaluronate [INCI: LocustBean (Ceratonia siliqua) Gum] or Preregen® [INCI: Glycine soja (Soybean)Protein, Oxido Reductases] marketed by Pentapharm/DSM, Myoxinol™ [INCI:Hydrolyzed Hibiscus esculentus Extract], Syniorage™ [INCI: AcetylTetrapeptide-11], Dermican™ [INCI: Acetyl Tetrapeptide-9] or DN AGE™ LS[INCI: Cassia alata leaf Extract] marketed by LaboratoiresSérobiologiques/Cognis/BASF, Algisum C® [INCI: MethylsilanolMannuronate] or Hydroxyprolisilane CN® [INCI: MethylsilanolHydroxyproline Aspartate] marketed by Exsymol, Argireline® [INCI: AcetylHexapeptide-8], SNAP-7 [INCI: Acetyl Heptapeptide-4], SNAP-8 [INCI:Acetyl Octapeptide-3], Leuphasyl® [INCI: Pentapeptide-18], Inyline™[INCI: Acetyl Hexapeptide-30], Aldenine® [INCI: Hydrolized WheatProtein, Hydrolized Soy Protein, Tripeptide-1], Preventhelia™ [INCI:Diaminopropionoyl Tripeptide-33], Decorinyl® [INCI: Tripeptide-10Citrulline], Decorinol® [INCI: Tripeptide-9 Citrulline], Trylagen®[INCI: Pseudoalteromonas Ferment Extract, Hydrolyzed Wheat Protein,Hydrolyzed Soy Protein, Tripeptide-10 Citrulline, Tripeptide-1],Eyeseryl® [INCI: Acetyl Tetrapeptide-5], Peptide AC29 [INCI: AcetylTripeptide-30 Citrulline], Relistase™ [INCI: AcetylarginyltriptophylDiphenylglycine], Thermostressine® [INCI: Acetyl Tetrapeptide-22],Lipochroman™ [INCI: Dimethylmethoxy Chromanol], Chromabright™ [INCI:Dimethylmethoxy Chromanyl Palmitate], Antarcticine® [INCI:Pseudoalteromonas Ferment Extract], dGlyage™ [INCI: Lysine HCl,Lecithin, Tripeptide-9 Citrulline], Vilastene™ [INCI: Lysine HCl,Lecithin, Tripeptide-10 Citrulline], Hyadisine™ [INCI: PseudoalteromonasFerment Extract], Hyanify™ [proposed INCI: Saccharide Isomerate],Diffuporine™ [INCI: Acetyl Hexapeptide-37], Silusyne™ [INCI: Soybean(Glycine Soja) Oil, Sorbitan Sesquioleate, Isohexadecane, SodiumHyaluronate, Lauryldimonium Hydroxypropyl Hydrolized Soy Protein, AcetylHexapeptide-39] or Adifyline™[INCI: Acetyl Hexapeptide-38] marketed byLipotec, Kollaren® [INCI: Tripeptide-1, Dextran] marketed by InstitutEuropeen de Biologie Cellulaire, Collaxyl® IS [INCI: Hexapeptide-9],Laminixyl IS™ [INCI: Heptapeptide], Orsirtine™ GL [INCI: Oryza sativa(Rice) Extract], D'Orientine™ IS [INCI: Phoenix dactylifera (Date) SeedExtract], Phytoquintescine™ [INCI: Einkorn (Triticum monococcum)Extract] or Quintescine™ IS [INCI: Dipeptide-4] marketed byVincience/ISP/Ashland, BONT-L-Peptide [INCI: Palmitoyl Hexapeptide-19]marketed by Infinitec Activos, Deepaline™ PVB [INCI: Palmitoylhydrolyzed Wheat Protein] or Sepilift® DPHP [INCI: DipalmitoylHydroxyproline] marketed by Seppic, Gatuline® Expression [INCI: Acmellaoleracea Extract], Gatuline® In-Tense [INCI: Spilanthes acmella FlowerExtract] or Gatuline® Age Defense 2 [INCI: Juglans regia (Walnut) SeedExtract] marketed by Gattefossé, Thalassine™ [INCI: Algae Extract]marketed by Biotechmarine, ChroNOline™ [INCI: Caprooyl Tetrapeptide-3]or Thymulen-4 [INCI: Acetyl Tetrapeptide-2] marketed by Atrium/UnipexInnovations, EquiStat [INCI: Pyrus malus Fruit Extract, Glycine sojaSeed Extract] or Juvenesce [INCI: Ethoxydiglicol and CaprylicTriglycerid, Retinol, Ursolic Acid, Phytonadione, Ilomastat] marketed byColetica/Engelhard/BASF, Ameliox [INCI: Carnosine, Tocopherol, Silybummarianum Fruit Extract] or PhytoCellTec Malus Domestica [INCI: Malusdomestica Fruit Cell Culture] marketed by Mibelle Biochemistry,Bioxilift [INCI: Pimpinella anisum Extract] or SMS Anti-Wrinkle® [INCI:Annona squamosa Seed Extract] marketed by Silab, antagonists of the Ca²⁺channel such as and not restricted to, alverine, manganese or magnesiumsalts, certain secondary or tertiary amines, retinol and itsderivatives, idebenone and its derivatives, Coenzyme Q10 and itsderivatives, boswellic acid and its derivatives, GHK and its derivativesand/or salts, carnosine and its derivatives, DNA repair enzymes such asand not restricted to, photolyase or T4 endonuclease V, or chloridechannel agonists among others, and/or mixtures thereof.

An additional aspect of this invention relates to a cosmetic orpharmaceutical composition which comprises a cosmetically orpharmaceutically effective amount of at least one compound of generalformula (I), its stereoisomers, mixtures thereof and/or its cosmeticallyor pharmaceutically acceptable salts, and, in addition, a cosmeticallyor pharmaceutically effective amount of at least one natural extract oressential oil which is an anti-itching agent, for example and notrestricted to, extracts of Abelmoschus esculentus, Actaea alba, Aglaiaodorata, Alkanna tinctoria, Althaea officinalis, Altingia excelsa,Andropogon virginicus, Aralia nudicaulis, Aralia racemosa, Argemonemexicana, Barleria prionitis, Camelia sinensis, Caesalpinia digyna,Campsis grandiflora, Carissa congesta, Carthamus oxyacantha, Cassiatora, Chrysanthemum indicum, Cimicifuga racemosa, Cinnamomum camphora,Clematis vitalba, Cuscuta reflexa, Diospyros peregrina, Enicostemaaxillare, Hammamelis virginiana, Jatropha multifida, Lavandulaofficinalis, Lavandula latifolia, Liquidambar orientalis, Lithospermumofficinale, Madhuca longifolia, Martynia annua, Medicago sativa,Michelia champaca, Mikania glomerata, Mimosa pudica, Oryza sativa,Phaseolus vulgaris, Phyllanthus urinaria, Phyllanthus virgatus, Pistaciavera, Polygonum hydropiper, Quercus ilex, Rauvolfia caffra, Ricinuscommunis, Rubus idaeus, Sagittaria sagittifolia, Sandoricum koetjape,Sapindus mukorossi, Schleichera oleosa, Sesbania grandiflora, Spondiasdulcis, Tilia sp., Toona ciliata, Tragia involucrata, Trichosanthesquinquangulata, Vaccaria pyramidata, Ventilago madraspatana, Veratrumalbum or Xanthium strumarium among others or as well as at least onesynthetic compound or product of biotechnological origin which is ananti-itching agent, for example and not restricted to, mepyramine(pyrilamine), antazoline, diphenhydramine, carbinoxamine, doxylamine,clemastine, dimenhydrinate, pheniramine, chlorphenamine(chlorpheniramine), dexchlorpheniramine, bronpheniramine, triprolidine,cyclizine, chlorcyclizine, hydroxyzine, meclizine, cetirizine,levocetirizine, promethazine, thenaldine, alimemazine (trimeprazine),cyproheptadine, azatidine, ketotifen, acrivastine, astemizole,cetirizine, loratadine, desloratadine, mizolastine, terfenadine,fexofenadine, azelastine, levocabastine, olopatadine, corticosteroidssuch as cortisone, hydrocortisone, dexamethasone, prednisone; Neutrazen™[INCI: Water, Butylene Glycol, Dextran, Palmitoyl Tripeptide-8] marketedby Atrium/Unipex Innovations, Meliprene® [INCI: Dextran, AcetilHeptapeptide-1] marketed by Institut Européen de BiologieCellulaire/Unipex Innovations, Delisens™ [proposed INCI: AcetylHexapeptide-46] marketed by Lipotec, Skinasensyl™ [INCI: AcetylTetrapeptide-15] marketed by Laboratoires Sérobiologiques/Cognis/BASF,SymSitive® 1609 [INCI: 4-t-Butylcyclohexanol] marketed by Symrise,Symbiocell™ [INCI: Extract from Cestrum Latifolium] marketed by BASF,Gatuline® Derma-Sensitive [INCI: Octyldodecyl Myristate, CapparisSpinosa Fruit Extract] marketed by Gattefossé or MAXnolia [INCI:Magnolia Officinalis Bark Extract, Vitis Vinifera/Vitis Vinifera (Grape)Seed Extract, Tocopherol] marketed by Mibelle Biochemistry among others,or mixtures thereof.

An additional aspect of this invention relates to a cosmetic orpharmaceutical composition containing a cosmetically or pharmaceuticallyeffective quantity of at least one compound of general formula (I), itsstereoisomers, mixtures thereof and/or its cosmetically orpharmaceutically acceptable salts, and also a cosmetically orpharmaceutically effective amount of at least one anti-inflammatoryagent and/or analgesic selected, for example and not restricted to, fromthe group formed by the extract of madecassoside, extract of echinacin,amaranth seed oil, sandalwood oil, peach tree leaf extract, extract ofAloe vera, Arnica montana, Artemisia vulgaris, Asarum maximum, Calendulaofficinalis, Capsicum, Centipeda cunninghamii, Chamomilla recutita,Crinum asiaticum, Hamamelis virginiana, Harpagophytum procumbens,Hypericum perforatum, Lilium candidum, Malva sylvestris, Melaleucaalternifolia, Origanum majorana, Origanum vulgare, Prunus laurocerasus,Rosmarinus officialis, Salix alba, Silybum marianum, Tanacetumparthenium, Thymus vulgaris, Uncaria guianensis or Vaccinum myrtillus,mometasone furoate, prednisolone, non-steroidal anti-inflammatory drugsincluding cyclooxygenase or lipoxygenase inhibitors, benzydamine,acetylsalicylic acid, rosmarinic acid, ursolic acid, glycyrrhizinatederivatives, α-bisabolol, azulene and analogs, sericoside, ruscogenin,escin, escoline, rutin and analogs, hydrocortisone, clobetasol,dexamethasone, halobetasol, diflorasone, fluocinonide, amcinonide,triamcinolone, fluticasone, fluocinolone, flurandrenolide,prednicarbate, prednisone, paracetamol, amoxiprin, benorilate, cholinesalicylate, faislamine, methyl salicylate, magnesium salicylate,salsalate, diclofenac, aceclofenac, acemetacin, bromfenac, etodolac,indomethacin, oxamethacin, proglumetacin, sulindac, tolmetin, ibuprofen,dexibuprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, ketoprofen,dexketoprofen, ketorolac, loxoprofen, naproxen, miroprofen, oxaprozin,pranoprofen, tiaprofenic acid, suprofen, mefenamic acid, meclofenamate,meclofenamic acid, flufenamic acid, tolfenamic acid, nabumetone,phenylbutazone, azapropazone, clofezone, kebuzone, metamizole,mofebutazone, oxyphenbutazone, phenazone, sulfinpyrazone, piroxicam,lornoxicam, meloxicam, tenoxicam, celecoxib, etoricoxib, lumiracoxib,parecoxib, rofecoxib, valdecoxib, nimesulide, naproxcinod, fluproquazoneor licofelone, omega-3 and omega-6 fatty acids, morphine, codeine,oxycodone, hydrocodone, diamorphine, pethidine, tramadol, buprenorphine,benzocaine, lidocaine, chloroprocaine, tetracaine, procaine,amitriptyline, carbamazepine, gabapentine, pregabaline, bisabolol,Neutrazen™ [INCI: Water, Butylene Glycol, Dextran, PalmitoylTripeptide-8] marketed by Atrium/Unipex Innovations, Delisens™ [proposedINCI: Acetyl Hexapeptide-46] marketed by Lipotec, Meliprene® [INCI:Dextran, Acetyl Heptapeptide-1] marketed by Institut Européen deBiologie Cellulaire/Unipex Innovations, Skinasensyl™ [INCI: AcetylTetrapeptide-15] or Anasensyl™ [INCI: Mannitol, Ammonium Glycyrrhizate,Caffeine, Hippocastanum (Horse Chestnut) Extract] marketed byLaboratoires Serobiologiques/Cognis/BASF, Calmosensine™ [INCI: AcetylDipeptide-1] marketed by Sederma/Croda, coenzyme Q10 or alkylglycerinethers, among others, or mixtures thereof.

Another additional aspect of this invention relates to a cosmetic orpharmaceutical composition containing a cosmetically or pharmaceuticallyeffective quantity of at least one compound of general formula (I), itsstereoisomers, mixtures thereof and/or its cosmetically orpharmaceutically acceptable salts, and also a cosmetically orpharmaceutically effective amount of at least one agent which inhibitsneuronal exocytosis, anticholinergic agent, inhibitor ofacetylcholine-receptor aggregation and/or a muscle contraction inhibitorselected, for example and not restricted to, from the group formed byextracts of Atropa belladonna, Hyoscyamus niger, Mandragora officinarum,Chondodendron tomentosum, plants from the Brugmansias genus, or from theDaturas genus, Clostridium botulinum toxin, peptides derived from theprotein SNAP-25, peptides derived from the protein synaptotagmin,peptides derived from the protein syntaxin, peptides derived from theprotein synaptobrevin, peptides derived from the protein snapin,baclofen, carbidopa, levodopa, bromocriptine, chlorphenesin,chlorzoxazone, donepezil, mephenoxalone, reserpine, tetrabenazine,dantrolene, thiocolchicoside, tizanidine, chlonidine, procyclidine,glycopyrrolate, atropine, hyoscyamine, benztropine, scopolamine,prometazine, diphenhydramine, dimenhydrinate, dicyclomine,cyclobenzaprine, orphenadrine, flavoxate, cyclopentolate, ipratropium,oxybutynin, pirenzepine, tiotropium, trihexyphenidyl, tolterodine,tropicamide, solifenacin, darifenacin, mebeverine, trimethaphan,atracurium, cisatracurium, doxacurium, fazadinium, metocurine,mivacurium, pancuronium, pipecuronium, rapacuronium, tubocuranine,dimethyl tubocuranine, rocuronium, vecuronium, suxamethonium,18-methoxycoronaridine, carisoprodol, febarbamate, meprobamate,metocarbamol, phenprobamate, tibamate, anticonvulsant agents such aslevetiracetam, stiripentol, phenobarbital, methylphenobarbital,pentobarbital, metarbital, barbexaclone, primidone, carbamazepine,oxcarbazepine, benzodiazepines, for example and not restricted to,clonazepam, cloxazolam, clorazepate, diazepam, flutoprazepam, lorazepam,midazolam, nitrazepam, nimetazepam, fenazepam, temazepam, tetrazepam,clobazam, Argireline® [INCI: Acetyl Hexapeptide-8], SNAP-7 [INCI: AcetylHeptapeptide-4], SNAP-8 [INCI: Acetyl Octapeptide-3], Leuphasyl® [INCI:Pentapeptide-18] or Inyline™ [INCI: Acetyl Hexapeptide-30] marketed byLipotec, BONT-L-Peptide [INCI: Palmitoyl Hexapeptide-19] marketed byInfinitec Activos, and Vialox® [INCI: Pentapeptide-3] or Syn® Ake®[INCI: Dipeptide Diaminobutyroyl Benzylamide Diacetate] marketed byPentapharm/DSM among others, or mixtures thereof.

Another additional aspect of this invention relates to a cosmetic orpharmaceutical composition containing a cosmetically or pharmaceuticallyeffective quantity of at least one compound of general formula (I), itsstereoisomers, mixtures thereof and/or its cosmetically orpharmaceutically acceptable salts, and also a cosmetically orpharmaceutically effective amount of at least one cosmetic and/orabsorbent and/or body odor masking deodorant and/or antiperspirantagent, perfume and/or perfumed oil selected, for example and notrestricted to, from the group formed by the complex zinc salt ofricinoleic acid, derived from abiotic acid, salvia essence, chamomileessence, carnation essence, lemon balm essence, mint essence, cinnamonleaf essence, lime blossom essence, juniper berry essence, vetiveressence, frankincense essence, galbanum essence, labdanum essence,lavender essence, peppermint essence, benzoin, bergamot,dihydromyrcenol, lilial, lyral, citronellol, lemon essence, mandarinessence, orange essence, lavender essence, muscatel, geranium bourbonessence, aniseed, cilantro, cumin, juniper, extracts of fleur-de-lis,lily, roses, jasmine, neroli; benzyl acetate, p-tert-butylcyclohexylacetate, linalyl acetate, phenylethyl acetate, ethylmethylphenylglycinate, linalyl benzoate, benzyl formiate, alylcyclohexyl propionate,stiralyl propionate, benzyl salicylate, benzylethylether, linear alkaneswith from 8 to 18 carbon atoms, citral, ricinoleic acid, citronellal,citronellyl oxyacetaldehyde, cyclamen aldehyde, hydroxycitronellal,bourgeonal, ionones, methyl cedryl ketone, anethole, eugenol,isoeugenol, geraniol, linalool, terpineol, phenylethylalcohol,α-hexylcinnamaldehyde, geraniol, benzylacetone, cyclamenaldehyde,ambroxan, indole, hedione, sandelice, cyclovertal, β-damascone, allylamyl glycolate, dihydromyrcenol, phenoxyethyl isobutyrate, cyclohexylsalicylate, phenylacetic acid, geranyl acetate, romilate, irotyl,floramate, aluminum salts such as alum, aluminum chloride, aluminumchlorohydrate, aluminum dichlorohydrate, aluminum sesquichlorohydrate,aluminum hydroxy allantoinate, aluminum chlorotartrate, aluminum andzirconium trichlorohydrate, aluminum and zirconium tetrachlorohydrate,aluminum and zirconium pentachlorohydrate and/or mixtures thereof,Leuphasyl® [INCI: Pentapeptide-18], SNAP-7 [INCI: AcetylHeptapeptide-4], SNAP-8 [INCI: Acetyl Octapeptide-3], Argireline® [INCI:Acetyl Hexapeptide-8] or Inyline™ [INCI: Acetyl Hexapeptide-30] marketedby Lipotec, Vialox® [INCI: Pentapeptide 3] or Syn® Ake® [INCI: DipeptideDiaminobutyroyl Benzylamide Diacetate] marketed by Pentapharm/DSM andBONT-L-Peptide [INCI: Palmitoyl Hexapeptide-19] marketed by InfinitecActivos among others, or mixtures thereof.

Applications

In another aspect, this invention relates to a compound of generalformula (I):R₁—W_(n)—X_(m)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-AA₇-Y_(p)—Z_(q)—R₂  (I)its stereoisomers, mixtures thereof and/or its cosmetically orpharmaceutically acceptable salts, characterized in that:

-   -   AA₁ is selected from the group formed by -Arg-, -His-, -Lys-,        -Gln-, -Asn-, -Glu- and -Asp-;    -   AA₂ is selected from the group formed by -His-, -Gln-, -Asn-,        -Glu- and -Asp-;    -   AA₃ is selected from the group formed by -Leu-, -Ile-, -Phe- and        -Tyr-;    -   AA₄ is selected from the group formed by -Lys-, -His-, -Arg-,        -Gln-, -Leu-, -Ile-, -Met-, -MetO— and -MetO₂—;    -   AA₅ is selected from the group formed by -Arg-, -His-, -Lys-,        -Gln-, -Asn-, -Glu- and -Asp-;    -   AA₆ is selected from the group formed by -Phe-, -Trp-, -Ile- and        -Val-;    -   AA₇ is selected from the group formed by -Met-, -MetO— and        -MetO₂—;    -   W, X, Y, Z are amino acids and are independently selected from        amongst themselves;    -   n, m, p and q are independently selected from amongst themselves        and have a value of 0 or 1;    -   n+m+p+q is smaller or equal to 2;    -   with the condition that it is not SEQ ID NO:111;    -   R₁ is selected from the group formed by H, a polymer derived        from polyethylene glycol, substituted or unsubstituted        non-cyclic aliphatic group, substituted or unsubstituted        alicyclyl, substituted or unsubstituted heterocyclyl,        substituted or unsubstituted heteroarylalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted aralkyl and        R₅—CO—, wherein R₅ is selected from the group formed by H,        substituted or unsubstituted non-cyclic aliphatic group,        substituted or unsubstituted alicyclyl, substituted or        unsubstituted aryl, substituted or unsubstituted aralkyl,        substituted or unsubstituted heterocyclyl and substituted or        unsubstituted heteroarylalkyl;    -   R₂ is selected from the group formed by —NR₃R₄, —OR₃ and —SR₃,        wherein R₃ and R₄ are independently selected from the group        formed by H, a polymer derived from polyethylene glycol,        substituted or unsubstituted non-cyclic aliphatic group,        substituted or unsubstituted alicyclyl, substituted or        unsubstituted heterocyclyl, substituted or unsubstituted        heteroarylalkyl, substituted or unsubstituted aryl, substituted        or unsubstituted aralkyl; and    -   R₁ and R₂ are not α-amino acids,        for its use in medicine.

In another aspect, the invention relates to a compound of generalformula (I):R₁—W_(n)—X_(m)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-AA₇-Y_(p)—Z_(q)—R₂  (I)

its stereoisomers, mixtures thereof and/or its cosmetically orpharmaceutically acceptable salts, characterized in that:

-   -   AA₁ is selected from the group formed by -Arg-, -His-, -Lys-,        -Gln-, -Asn-, -Glu- and -Asp-;    -   AA₂ is selected from the group formed by -His-, -Gln-, -Asn-,        -Glu- and -Asp-;    -   AA₃ is selected from the group formed by -Leu-, -Ile-, -Phe- and        -Tyr-;    -   AA₄ is selected from the group formed by -Lys-, -His-, -Arg-,        -Gln-, -Leu-, -Ile-, -Met-, -MetO— and -MetO₂—;    -   AA₅ is selected from the group formed by -Arg-, -His-, -Lys-,        -Gln-, -Asn-, -Glu- and -Asp-;    -   AA₆ is selected from the group formed by -Phe-, -Trp-, -Ile- and        -Val-;    -   AA₇ is selected from the group formed by -Met-, -MetO— and        -MetO₂—;    -   W, X, Y, Z are amino acids and are independently selected from        amongst themselves;    -   n, m, p and q are independently selected from amongst themselves        and have a value of 0 or 1;    -   n+m+p+q is smaller or equal to 2;    -   R₁ is selected from the group formed by H, a polymer derived        from polyethylene glycol, substituted or unsubstituted        non-cyclic aliphatic group, substituted or unsubstituted        alicyclyl, substituted or unsubstituted heterocyclyl,        substituted or unsubstituted heteroarylalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted aralkyl and        R₅—CO—, wherein R₅ is selected from the group formed by H,        substituted or unsubstituted non-cyclic aliphatic group,        substituted or unsubstituted alicyclyl, substituted or        unsubstituted aryl, substituted or unsubstituted aralkyl,        substituted or unsubstituted heterocyclyl and substituted or        unsubstituted heteroarylalkyl;    -   R₂ is selected from the group formed by —NR₃R₄, —OR₃ and —SR₃,        wherein R₃ and R₄ are independently selected from the group        formed by H, a polymer derived from polyethylene glycol,        substituted or unsubstituted non-cyclic aliphatic group,        substituted or unsubstituted alicyclyl, substituted or        unsubstituted heterocyclyl, substituted or unsubstituted        heteroarylalkyl, substituted or unsubstituted aryl, substituted        or unsubstituted aralkyl; and    -   R₁ and R₂ are not α-amino acids,        for its use in the treatment and/or prevention, delaying or        hindering of pain, inflammation, itching, hyperhidrosis and/or        of neurological, compulsive and/or neuropsychiatric diseases        and/or disorders which are improved by the inhibition of        neuronal exocytosis, selected from the group formed by muscular        spasticity, dystonia, focal dystonia, blepharospasm, torsion        dystonia, cervical dystonia or torticollis, laryngeal dystonia        or spasmodic dysphonia, oromandibular dystonia, extremity        dystonia, writer's cramp, musician's cramp, foot dystonia,        bruxism, facial scoliosis, hemifacial spasm, tics, strabismus,        segmentary dystonia, Meige's syndrome, multifocal dystonia,        hemidystonia, dopamine-responsive dystonia, Segawa's dystonia,        trembling, Parkinson's disease, nerve impingements, Alzheimer's        disease and Tourette's syndrome.

In another aspect, the invention relates to a compound of generalformula (I):R₁—W_(n)—X_(m)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-AA₇-Y_(p)—Z_(q)—R₂  (I)its stereoisomers, mixtures thereof and/or its cosmetically orpharmaceutically acceptable salts, characterized in that:

-   -   AA₁ is selected from the group formed by -Arg-, -His-, -Lys-,        -Gln-, -Asn-, -Glu- and -Asp-;    -   AA₂ is selected from the group formed by -His-, -Gln-, -Asn-,        -Glu- and -Asp-;    -   AA₃ is selected from the group formed by -Leu-, -Ile-, -Phe- and        -Tyr-;    -   AA₄ is selected from the group formed by -Lys-, -His-, -Arg-,        -Gln-, -Leu-, -Ile-, -Met-, -MetO— and -MetO₂—;    -   AA₅ is selected from the group formed by -Arg-, -His-, -Lys-,        -Gln-, -Asn-, -Glu- and -Asp-;    -   AA₆ is selected from the group formed by -Phe-, -Trp-, -Ile- and        -Val-;    -   AA₇ is selected from the group formed by -Met-, -MetO— and        -MetO₂—;    -   W, X, Y, Z are amino acids and are independently selected from        amongst themselves;    -   n, m, p and q are independently selected from amongst themselves        and have a value of 0 or 1;    -   n+m+p+q is smaller or equal to 2;    -   R₁ is selected from the group formed by H, a polymer derived        from polyethylene glycol, substituted or unsubstituted        non-cyclic aliphatic group, substituted or unsubstituted        alicyclyl, substituted or unsubstituted heterocyclyl,        substituted or unsubstituted heteroarylalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted aralkyl and        R₅—CO—, wherein R₅ is selected from the group formed by H,        substituted or unsubstituted non-cyclic aliphatic group,        substituted or unsubstituted alicyclyl, substituted or        unsubstituted aryl, substituted or unsubstituted aralkyl,        substituted or unsubstituted heterocyclyl and substituted or        unsubstituted heteroarylalkyl;    -   R₂ is selected from the group formed by —NR₃R₄, —OR₃ and —SR₃,        wherein R₃ and R₄ are independently selected from the group        formed by H, a polymer derived from polyethylene glycol,        substituted or unsubstituted non-cyclic aliphatic group,        substituted or unsubstituted alicyclyl, substituted or        unsubstituted heterocyclyl, substituted or unsubstituted        heteroarylalkyl, substituted or unsubstituted aryl, substituted        or unsubstituted aralkyl; and    -   R₁ and R₂ are not α-amino acids,        for its use in the treatment of the skin, hair and/or mucous        membranes.

In another aspect, the invention relates to the use of a compound ofgeneral formula (I):R₁—W_(n)—X_(m)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-AA₇-Y_(p)—Z_(q)—R₂  (I)its stereoisomers, mixtures thereof and/or its cosmetically orpharmaceutically acceptable salts, characterized in that:

-   -   AA₁ is selected from the group formed by -Arg-, -His-, -Lys-,        -Gln-, -Asn-, -Glu- and -Asp-;    -   AA₂ is selected from the group formed by -His-, -Gln-, -Asn-,        -Glu- and -Asp-;    -   AA₃ is selected from the group formed by -Leu-, -Ile-, -Phe- and        -Tyr-;    -   AA₄ is selected from the group formed by -Lys-, -His-, -Arg-,        -Gin-, -Leu-, -Ile-, -Met-, -MetO— and -MetO₂—;    -   AA₅ is selected from the group formed by -Arg-, -His-, -Lys-,        -Gln-, -Asn-, -Glu- and -Asp-;    -   AA₆ is selected from the group formed by -Phe-, -Trp-, -Ile- and        -Val-;    -   AA₇ is selected from the group formed by -Met-, -MetO— and        -MetO₂—;    -   W, X, Y, Z are amino acids and are independently selected from        amongst themselves;    -   n, m, p and q are independently selected from amongst themselves        and have a value of 0 or 1;    -   n+nn+p+q is smaller or equal to 2;    -   R₁ is selected from the group formed by H, a polymer derived        from polyethylene glycol, substituted or unsubstituted        non-cyclic aliphatic group, substituted or unsubstituted        alicyclyl, substituted or unsubstituted heterocyclyl,        substituted or unsubstituted heteroarylalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted aralkyl and        R₅—CO—, wherein R₅ is selected from the group formed by H,        substituted or unsubstituted non-cyclic aliphatic group,        substituted or unsubstituted alicyclyl, substituted or        unsubstituted aryl, substituted or unsubstituted aralkyl,        substituted or unsubstituted heterocyclyl and substituted or        unsubstituted heteroarylalkyl;    -   R₂ is selected from the group formed by —NR₃R₄, —OR₃ and —SR₃,        wherein R₃ and R₄ are independently selected from the group        formed by H, a polymer derived from polyethylene glycol,        substituted or unsubstituted non-cyclic aliphatic group,        substituted or unsubstituted alicyclyl, substituted or        unsubstituted heterocyclyl, substituted or unsubstituted        heteroarylalkyl, substituted or unsubstituted aryl, substituted        or unsubstituted aralkyl; and    -   R₁ and R₂ are not α-amino acids,        for the cosmetic, non-therapeutic treatment and/or care of the        skin, hair and/or mucous membranes, in particular for the        prevention, delay or hindering of aging and/or photoaging of the        skin, hair and/or mucous membranes, the treatment and/or        prevention, delay or hindering of wrinkles and/or expression        wrinkles, treatment and/or prevention, delay or hindering of        perspiration, treatment and/or care of disorders of the skin        selected from the group formed by calluses, warts, treatment        stimulating hair growth and/or prevention, delay or hindering of        hair loss.

In another aspect the invention relates to a compound of general formula(I):R₁—W_(n)—X_(m)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-AA₇-Y_(p)—Z_(q)—R₂  (I)its stereoisomers, mixtures thereof and/or its cosmetically orpharmaceutically acceptable salts, characterized in that:

-   -   AA₁ is selected from the group formed by -Arg-, -His-, -Lys-,        -Gln-, -Asn-, -Glu- and -Asp-;    -   AA₂ is selected from the group formed by -His-, -Gln-, -Asn-,        -Glu- and -Asp-;    -   AA₃ is selected from the group formed by -Leu-, -Ile-, -Phe- and        -Tyr-;    -   AA₄ is selected from the group formed by -Lys-, -His-, -Arg-,        -Gin-, -Leu-, -Ile-, -Met-, -MetO— and -MetO₂—;    -   AA₅ is selected from the group formed by -Arg-, -His-, -Lys-,        -Gln-, -Asn-, -Glu- and -Asp-;    -   AA₆ is selected from the group formed by -Phe-, -Trp-, -Ile- and        -Val-;    -   AA₇ is selected from the group formed by -Met-, -MetO— and        -MetO₂—;    -   W, X, Y, Z are amino acids and are independently selected from        amongst themselves;    -   n, m, p and q are independently selected from amongst themselves        and have a value of 0 or 1;    -   n+m+p+q is smaller or equal to 2;    -   R₁ is selected from the group formed by H, a polymer derived        from polyethylene glycol, substituted or unsubstituted        non-cyclic aliphatic group, substituted or unsubstituted        alicyclyl, substituted or unsubstituted heterocyclyl,        substituted or unsubstituted heteroarylalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted aralkyl and        R₅—CO—, wherein R₅ is selected from the group formed by H,        substituted or unsubstituted non-cyclic aliphatic group,        substituted or unsubstituted alicyclyl, substituted or        unsubstituted aryl, substituted or unsubstituted aralkyl,        substituted or unsubstituted heterocyclyl and substituted or        unsubstituted heteroarylalkyl;    -   R₂ is selected from the group formed by —NR₃R₄, —OR₃ and —SR₃,        wherein R₃ and R₄ are independently selected from the group        formed by H, a polymer derived from polyethylene glycol,        substituted or unsubstituted non-cyclic aliphatic group,        substituted or unsubstituted alicyclyl, substituted or        unsubstituted heterocyclyl, substituted or unsubstituted        heteroarylalkyl, substituted or unsubstituted aryl, substituted        or unsubstituted aralkyl; and    -   R₁ and R₂ are not α-amino acids,        for its use in the inhibition of neuronal exocytosis.

Alternatively, in another aspect, the invention relates to a method oftreatment and/or prevention, delay or hindering of pain, inflammation,itching, hyperhidrosis and/or of neurological, compulsive and/orneuropsychiatric diseases and/or disorders which are improved by theinhibition of neuronal exocytosis, selected from the group formed bymuscular spasticity, dystonia, focal dystonia, blepharospasm, torsiondystonia, cervical dystonia or torticollis, laryngeal dystonia orspasmodic dysphonia, oromandibular dystonia, extremity dystonia,writer's cramp, musician's cramp, foot dystonia, bruxism, facialscoliosis, hemifacial spasm, tics, strabismus, segmentary dystonia,Meige's syndrome, multifocal dystonia, hemidystonia, dopamine-responsivedystonia, Segawa's dystonia, trembling, Parkinson's disease, nerveimpingements, Alzheimer's disease and Tourette's syndrome, whichcomprises the administration of a cosmetically or pharmaceuticallyeffective quantity of at least one compound of general formula (I):R₁—W_(n)—X_(m)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-AA₇-Y_(p)—Z_(q)—R₂  (I)

its stereoisomers, mixtures thereof and/or its cosmetically orpharmaceutically acceptable salts, characterized in that:

-   -   AA₁ is selected from the group formed by -Arg-, -His-, -Lys-,        -Gln-, -Asn-, -Glu- and -Asp-;    -   AA₂ is selected from the group formed by -His-, -Gln-, -Asn-,        -Glu- and -Asp-;    -   AA₃ is selected from the group formed by -Leu-, -Ile-, -Phe- and        -Tyr-;    -   AA₄ is selected from the group formed by -Lys-, -His-, -Arg-,        -Gln-, -Leu-, -Ile-, -Met-, -MetO— and -MetO₂—;    -   AA₅ is selected from the group formed by -Arg-, -His-, -Lys-,        -Gln-, -Asn-, -Glu- and -Asp-;    -   AA₆ is selected from the group formed by -Phe-, -Trp-, -Ile- and        -Val-;    -   AA₇ is selected from the group formed by -Met-, -MetO— and        -MetO₂—;    -   W, X, Y, Z are amino acids and are independently selected from        amongst themselves;    -   n, m, p and q are independently selected from amongst themselves        and have a value of 0 or 1;    -   n+m+p+q is smaller or equal to 2;    -   R₁ is selected from the group formed by H, a polymer derived        from polyethylene glycol, substituted or unsubstituted        non-cyclic aliphatic group, substituted or unsubstituted        alicyclyl, substituted or unsubstituted heterocyclyl,        substituted or unsubstituted heteroarylalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted aralkyl and        R₅—CO—, wherein R₅ is selected from the group formed by H,        substituted or unsubstituted non-cyclic aliphatic group,        substituted or unsubstituted alicyclyl, substituted or        unsubstituted aryl, substituted or unsubstituted aralkyl,        substituted or unsubstituted heterocyclyl and substituted or        unsubstituted heteroarylalkyl;    -   R₂ is selected from the group formed by —NR₃R₄, —OR₃ and —SR₃,        wherein R₃ and R₄ are independently selected from the group        formed by H, a polymer derived from polyethylene glycol,        substituted or unsubstituted non-cyclic aliphatic group,        substituted or unsubstituted alicyclyl, substituted or        unsubstituted heterocyclyl, substituted or unsubstituted        heteroarylalkyl, substituted or unsubstituted aryl, substituted        or unsubstituted aralkyl; and    -   R₁ and R₂ are not α-amino acids.

In another aspect, the invention relates to a method of treatment and/orcare of the skin, hair and/or mucous membranes which comprises theadministration of a cosmetically or pharmaceutically effective quantityof at least one compound of general formula (I):R₁—W_(n)—X_(m)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-AA₇-Y_(p)—Z_(q)—R₂  (I)its stereoisomers, mixtures thereof and/or its cosmetically orpharmaceutically acceptable salts, characterized in that:

-   -   AA₁ is selected from the group formed by -Arg-, -His-, -Lys-,        -Gln-, -Asn-, -Glu- and -Asp-;    -   AA₂ is selected from the group formed by -His-, -Gln-, -Asn-,        -Glu- and -Asp-;    -   AA₃ is selected from the group formed by -Leu-, -Ile-, -Phe- and        -Tyr-;    -   AA₄ is selected from the group formed by -Lys-, -His-, -Arg-,        -Gln-, -Leu-, -Ile-, -Met-, -MetO— and -MetO₂—;    -   AA₅ is selected from the group formed by -Arg-, -His-, -Lys-,        -Gln-, -Asn-, -Glu- and -Asp-;    -   AA₆ is selected from the group formed by -Phe-, -Trp-, -Ile- and        -Val-;    -   AA₇ is selected from the group formed by -Met-, -MetO— and        -MetO₂—;    -   W, X, Y, Z are amino acids and are independently selected from        amongst themselves;    -   n, m, p and q are independently selected from amongst themselves        and have a value of 0 or 1;    -   n+m+p+q is smaller or equal to 2;    -   R₁ is selected from the group formed by H, a polymer derived        from polyethylene glycol, substituted or unsubstituted        non-cyclic aliphatic group, substituted or unsubstituted        alicyclyl, substituted or unsubstituted heterocyclyl,        substituted or unsubstituted heteroarylalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted aralkyl and        R₅—CO—, wherein R₅ is selected from the group formed by H,        substituted or unsubstituted non-cyclic aliphatic group,        substituted or unsubstituted alicyclyl, substituted or        unsubstituted aryl, substituted or unsubstituted aralkyl,        substituted or unsubstituted heterocyclyl and substituted or        unsubstituted heteroarylalkyl;    -   R₂ is selected from the group formed by —NR₃R₄, —OR₃ and —SR₃,        wherein R₃ and R₄ are independently selected from the group        formed by H, a polymer derived from polyethylene glycol,        substituted or unsubstituted non-cyclic aliphatic group,        substituted or unsubstituted alicyclyl, substituted or        unsubstituted heterocyclyl, substituted or unsubstituted        heteroarylalkyl, substituted or unsubstituted aryl, substituted        or unsubstituted aralkyl; and    -   R₁ and R₂ are not α-amino acids.

In another aspect the invention relates to a method of inhibition ofneuronal exocytosis which comprises the administration of a cosmeticallyor pharmaceutically effective quantity of at least a compound of generalformula (I):R₁—W_(n)—X_(m)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-AA₇-Y_(p)—Z_(q)—R₂  (I)

its stereoisomers, mixtures thereof and/or its cosmetically orpharmaceutically acceptable salts, characterized in that:

-   -   AA₁ is selected from the group formed by -Arg-, -His-, -Lys-,        -Gln-, -Asn-, -Glu- and -Asp-;    -   AA₂ is selected from the group formed by -His-, -Gln-, -Asn-,        -Glu- and -Asp-;    -   AA₃ is selected from the group formed by -Leu-, -Ile-, -Phe- and        -Tyr-;    -   AA₄ is selected from the group formed by -Lys-, -His-, -Arg-,        -Gln-, -Leu-, -Ile-, -Met-, -MetO— and -MetO₂—;    -   AA₅ is selected from the group formed by -Arg-, -His-, -Lys-,        -Gln-, -Asn-, -Glu- and -Asp-;    -   AA₆ is selected from the group formed by -Phe-, -Trp-, -Ile- and        -Val-;    -   AA₇ is selected from the group formed by -Met-, -MetO— and        -MetO₂—;    -   W, X, Y, Z are amino acids and are independently selected from        amongst themselves;    -   n, m, p and q are independently selected from amongst themselves        and have a value of 0 or 1;    -   n+m+p+q is smaller or equal to 2;    -   R₁ is selected from the group formed by H, a polymer derived        from polyethylene glycol, substituted or unsubstituted        non-cyclic aliphatic group, substituted or unsubstituted        alicyclyl, substituted or unsubstituted heterocyclyl,        substituted or unsubstituted heteroarylalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted aralkyl and        R₅—CO—, wherein R₅ is selected from the group formed by H,        substituted or unsubstituted non-cyclic aliphatic group,        substituted or unsubstituted alicyclyl, substituted or        unsubstituted aryl, substituted or unsubstituted aralkyl,        substituted or unsubstituted heterocyclyl and substituted or        unsubstituted heteroarylalkyl;    -   R₂ is selected from the group formed by —NR₃R₄, —OR₃ and —SR₃,        wherein R₃ and R₄ are independently selected from the group        formed by H, a polymer derived from polyethylene glycol,        substituted or unsubstituted non-cyclic aliphatic group,        substituted or unsubstituted alicyclyl, substituted or        unsubstituted heterocyclyl, substituted or unsubstituted        heteroarylalkyl, substituted or unsubstituted aryl, substituted        or unsubstituted aralkyl; and    -   R₁ and R₂ are not α-amino acids.

In accordance with a preferred embodiment, R₁ is selected from the groupformed by H, a polymer derived from polyethylene glycol and R₅—CO—, isselected from the group formed by substituted or unsubstituted alkylradical C₁-C₂₄, substituted or unsubstituted alkenyl C₂-C₂₄, substitutedor unsubstituted alkynyl C₂-C₂₄, substituted or unsubstituted cycloalkylC₃-C₂₄, substituted or unsubstituted cycloalkenyl C₅-C₂₄, substituted orunsubstituted cycloalkynyl C₈-C₂₄, substituted or unsubstituted arylC₆-C₃₀, substituted or unsubstituted aralkyl C₇-C₂₄, substituted orunsubstituted heterocyclyl ring of 3-10 members, and substituted orunsubstituted heteroarylalkyl of 2 to 24 carbon atoms and 1 to 3 atomsother than carbon and an alkyl chain of 1 to 6 carbon atoms and R₅—CO isnot an α-amino acid. More preferably, R₁ is selected from the groupformed by H, a polymer derived from polyethylene glycol of a molecularweight comprised between 200 and 35000 Daltons, acetyl, tert-butanoyl,prenyl, hexanoyl, 2-methylhexanoyl, cyclohexanecarboxyl, octanoyl,decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl and linoleoyl.Even more preferably, R₁ is H, acetyl, lauroyl, myristoyl or palmitoyl.In an even more preferable embodiment, R₁ is acetyl or palmitoyl.

In accordance with another preferred embodiment, R₂ is selected from thegroup formed by —NR₃R₄, —OR₃, —SR₃, wherein R₃ and R₄ are independentlyselected from the group formed by H, a polymer derived from polyethyleneglycol, substituted or unsubstituted alkyl C₁-C₂₄, substituted orunsubstituted alkenyl C₂-C₂₄, substituted or unsubstituted alkynylC₂-C₂₄, substituted or unsubstituted cycloalkyl C₃-C₂₄, substituted orunsubstituted cycloalkenyl C₅-C₂₄, substituted or unsubstitutedcycloalkynyl C₈-C₂₄, substituted or unsubstituted aryl C₆-C₃₀,substituted or unsubstituted aralkyl C₇-C₂₄, substituted orunsubstituted heterocyclyl ring of 3-10 members, and substituted orunsubstituted heteroarylalkyl of 2 to 24 carbon atoms and 1 to 3 atomsother than carbon wherein the alkyl chain is of 1 to 6 carbon atoms and—NR₃R₄ is not an α-amino acid. Optionally, R₃ and R₄ can be bound by asaturated or unsaturated carbon-carbon bond, forming a cycle with thenitrogen atom. More preferably R₂ is —NR₃R₄ or —OR₃. More preferably, R₃and R₄ are selected from the group formed by H, a polymer derived frompolyethylene glycol of a molecular weight comprised between 200 and35000 Daltons, methyl, ethyl, hexyl, dodecyl and hexadecyl. Even morepreferably R₃ is H and R₄ is selected from the group formed by H,methyl, ethyl, hexyl, dodecyl and hexadecyl. In accordance with an evenmore preferred embodiment, R₂ is selected from —OH and —NH₂.

In accordance with another preferred embodiment AA₁ is selected from thegroup formed by -Arg-, -Lys-, -Gln-, -Asn-, -Glu- and -Asp-, AA₂ isselected from the group formed by -His-, -Gln-, -Asn-, -Glu- and -Asp-,AA₃ is selected from the group formed by -Leu- and -Phe-, AA₄ isselected from the group formed by -His-, -Lys-, -Gln- and -Leu-, AA₅ isselected from the group formed by -Arg-, -His-, -Lys-, -Gin-, -Asn-,-Glu- and -Asp-, AA₆ is selected from the group formed by -Trp- and-Val- and AA₇ is selected from the group formed by -Met-, -MetO— and-MetO₂—. More preferably, AA₄ is selected from the group formed by -Lys-and -Leu-, and AA₆ is -Trp-. Even more preferably, n, m, p and q are 0.

In accordance with another embodiment of this invention R₁ is selectedfrom the group formed by H, acetyl, lauroyl, myristoyl and palmitoyl,AA₁ is selected from the group formed by -L-Arg-, -L-Lys-, -L-Gln-,-L-Asn-, -L-Glu- and -L-Asp-, AA₂ is selected from the group formed by-L-His-, -L-Gln-, L-Asn-, -L-Glu- and -L-Asp-, AA₃ is selected from thegroup formed by -L-Leu- and -L-Phe-, AA₄ is selected from the groupformed by -L-His-, -L-Lys-, -L-Gln- and -L-Leu-, AA₅ is selected fromthe group formed by -L-Arg-, -L-His-, -L-Lys-, -L-Gln-, -L-Asn-, -L-Glu-and -L-Asp-, AA₆ is selected from the group formed by -L-Trp- and-L-Val-, AA₇ is selected from the group formed by -L-Met-, -L-MetO— and-L-MetO₂—, and R₂ is selected from the group formed by —NR₃R₄ and —OR₃where R₃ and R₄ are independently selected from H, methyl, ethyl, hexyl,dodecyl and hexadecyl. More preferably, AA₄ is selected from the groupformed by -L-Lys- and -L-Leu-, and AA₆ is -L-Trp-. More preferably, R₁is acetyl or palmitoyl and R₂ is —NH₂. Even more preferably, n, m, p andq are 0.

In accordance with another even more preferred embodiment R₁ is selectedfrom the group formed by H, acetyl, lauroyl, myristoyl and palmitoyl,AA₁ is selected from the group formed by -L-Asn-, -L-Glu- and -L-Asp-,AA₂ is selected from the group formed by -L-His- and -L-Asp-, AA₃ isselected from the group formed by -L-Leu- and -L-Phe-, AA₄ is selectedfrom the group formed by -L-Lys-, -L-Gln- and -L-Leu-, AA₅ is selectedfrom the group formed by -L-Arg-, -L-Gln-, -L-Asn- and -L-Asp-, AA₆ isselected from the group formed by -L-Trp-, AA₇ is selected from thegroup formed by -L-Met-, -L-MetO— and -L-MetO₂— and R₂ is selected fromthe group formed by —NR₃R₄ and —OR₃ wherein R₃ and R₄ are independentlyselected from H, methyl, ethyl, hexyl, dodecyl and hexadecyl.

In accordance with another embodiment of this invention R₁ is selectedfrom the group formed by H, acetyl, lauroyl, myristoyl and palmitoyl,AA₁ is -L-Glu-, AA₂ is selected from the group formed by -L-Asn-,-L-Glu-, -L-Gln- and -L-Asp-, AA₃ is -L-Leu-, AA₄ is -L-Lys-, AA₅ is-L-Arg-, AA₆ is -L-Trp-, AA₇ is selected from the group formed by-L-Met-, -L-MetO— and -L-MetO₂—, and R₂ is selected from the groupformed by —NR₃R₄ and —OR₃ where R₃ and R₄ are independently selectedfrom H, methyl, ethyl, hexyl, dodecyl and hexadecyl. More preferably, R₁is acetyl or palmitoyl and R₂ is —NH₂. Even more preferably, n, m, p andq are 0.

In a preferred embodiment, the itching is selected from itchingassociated with conditions, diseases and/or disorders, for example andnot restricted to, dermatitis, atopic dermatitis, contact dermatitis,diaper dermatitis, dermatitis herpetiformis, photodermatosis,photosensitivity, pregnancy related dermatitis, menopause relateddermatitis, eczema, sensitive skin, psoriasis, chickenpox, herpes,herpes zoster, Netherton's syndrome, peeling skin syndrome, lichenplanus, acne, dandruff, seborrhea, seborrheic dermatitis, alopecia,athlete's foot, candidiasis, hemorrhoids, vaginal itching, perianalitching, anogenital itching, sunburn, hives, pruritic otitis, itchyeyes, senile pruritus, aquagenic pruritus, prurigo nodularis, prurigoplanus, pityriasis rosea, xerosis and dry skin, or itching associatedwith dialysis, infection from human immunodeficiency virus, malignantneoplasms, Hodgkin's disease, leukemia, myeloma, lymphoma, solid tumors,adenocarcinoma, lung cancer, hepatic diseases, jaundice, cholestasis,liver failure, cirrhosis, polycythemia, hypereosinophilic syndrome,essential thrombocythemia, myelodysplastic syndrome, iron-deficiencyanemia, systemic lupus erythematosus, endocrine diseases, thyroiddiseases, hyperthyroidism, hypothyroidism, parathyroid diseases,diabetes mellitus, kidney diseases, kidney failure, uremia, parasiticdiseases, scabies, lice, intestinal worms, allergic reactions, allergiesto medicines, food allergies, allergies to chemical products, exposureto poisonous plants, exposure to insect bites, chemotherapy, stress andanxiety, among others.

In another particular embodiment, the pain is selected, for example andnot restricted to, from the group formed by acute pain, chronic pain,nociceptive pain, neuropathic pain, inflammatory pain, visceral pain,abdominal pain, digestive system pain, respiratory system pain,urogenital system pain, endocrine system pain, heart pain, pancreaticpain, liver pain, pain due to gallstones, cholestasis, intestinal pain,stomach pain, pain due to duodenal ulcers, pain due to esophagitis, paindue to gastroesophageal reflux, spleen pain, blood vessel pain, thalamicpain syndrome, irritable bowel syndrome, pain associated with Crohn'sdisease, pain associated with ulcerative colitis, diverticulitis,gastrointestinal mucositis, headache, tension-type headache,sinusitis-associated headache, migraine, eye pain, dry eye syndrome,post-operative pain, post-operative pain due to surgical incisions,post-operative pain due to bone grafting, post-operative pain due tobone substitution, post-operative pain due to infections, post-operativepain due to limb amputations, pain due to bone fractures, pain due tocancer, pain due to bone cancer, pain associated with benign bonetumors, pain associated with osteoid osteomas, pain associated withosteoblastomas, pain due to cancer treatment, pain due to chemotherapy,pain due to emesis, pain due to emesis as a consequence of chemotherapytreatment, musculoskeletal pain, spastic muscle pain, fibromyalgia,complex regional pain syndrome, psychogenic pain, neuralgic pain, paindue to demyelinating diseases, neck pain associated with cervicaldystonia, back pain, lumbago, sciatica, neurogenic inflammation,neuritis, causalgia, touch sensitivity, sensitivity to cold, sensitivityto heat, cutaneous irritation, post-hair removal cutaneous irritation,post-shaving cutaneous irritation, psoriasis, sensitive skin,dermatitis, atopic dermatitis, contact dermatitis, diaper dermatitis,seborrheic dermatitis, eczema, lichen planus, burns, sunburn, arthritis,rheumatoid arthritis, osteoarthritis, psoriatic arthritis, uveitis, paindue to nerve lesions, neuralgia, postherpetic neuralgia, neuropathies,peripheral neuropathies, phantom pains, allodynia, hyperalgesia, coldhyperalgesia, pain due to carpal tunnel syndrome, burning pain,Grierson-Gopalan syndrome (better known as burning feet syndrome),burning mouth syndrome, paresthesias, Fabry's disease, facial pain,trigeminal neuralgia, neuropathic pain due to diabetes, neuropathic paindue to AIDS, orofacial pain, dental pain, pain due to tooth extraction,pain due to wisdom tooth extraction, tooth sensitivity to cold, toothsensitivity to heat, oral mucositis, temporomandibular joint pain, jointpain caused by gout, pain associated with tattooing or tattoo removalprocesses, pain due to bunions, testicular pain, myofascial pain,urinary bladder pain, urinary tract pain, cystitis, pain due to kidneystones, renal colic, vulvar pain, vaginal pain, post-birth pain,menstrual pain, scrotal pain, perineal pain, pelvic pain orhypersensitivity, cutaneous pain or irritation after surgery, afterintense pulsed light treatment (IPL), after treatment with monochromaticpulsed light (laser), after a treatment with chemical flaking agents orafter overexposure to external aggressive agents and pain due to chronicalcoholism, among others.

In another particular embodiment, inflammation is selected, for exampleand not restricted to, from the group formed by neurogenic inflammation,joint inflammation, tendon inflammation, muscular inflammation, sepsis,vascular inflammation, respiratory inflammation, chronic obstructivepulmonary disease, rhinitis, allergic rhinitis, asthma, otitis,intestinal inflammation, Crohn's disease, pancreatitis, hepatitis,conditions related to chronic inflammation, to acute inflammation,nephritis, systemic lupus erythematosus, arthritis, rheumatoidarthritis, adult and juvenile rheumatoid arthritis, Still's disease,psoriatic arthritis, osteoarthritis, arthritis caused by gout,rheumatoid spondylitis, glomerulonephritis, neuritis, inflammation ofthe nerve tissue, multiple sclerosis, immunological system disorders,Sjögren's syndrome, atherosclerosis, myocarditis, pericarditis,vasculitis, inflammatory skin conditions, psoriasis, sensitive skin,dermatitis, atopic dermatitis, contact dermatitis, diaper dermatitis,seborrheic dermatitis, eczema, rosacea, acne, hyperproliferative skindisease, burns, sunburn, cutaneous inflammation after surgery, afterintense pulsed light treatment (IPL), after treatment with monochromaticpulsed light (laser), after a treatment with chemical flaking agents orafter overexposure to external aggressive agents, inflammation of thevaginal mucous membranes, vulvodynia, vaginitis, inflammation of theoral mucous membranes, gingivitis, periodontitis, inflammatory eyediseases, uveitis, ocular and vernal conjunctivitis, sarcoidosis, pepticulcers, urticaria, bullous pemphigoid, scleroderma, fibrosis,angioedema, anaphylaxis, alopecia, hepatic cirrhosis, restenosis,polymyalgia rheumatica, seronegative spondyloarthropathies, includingankylosing spondylitis and Reiter's disease, dermatomyositis, inclusionbody myositis, polymyositis and lymphangioleiomyomatosis, among others.

In another particular embodiment, the neurological, compulsive andneuropsychiatric diseases and/or disorders which are improved byinhibition of neuronal exocytosis are selected, for example and notrestricted to, from the group formed by muscular spasticity, dystonia,and more specifically focal dystonia such as blepharospasm, torsiondystonia, cervical dystonia or torticollis, laryngeal dystonia orspasmodic dysphonia, oromandibular dystonia, extremity dystonia such aswriter's cramp, musician's cramp or foot dystonia, bruxism, facialscoliosis, hemifacial spasm, tics and/or strabismus; segmentarydystonia, Meige's syndrome, multifocal dystonia, hemidystonia,dopamine-responsive dystonia, Segawa's dystonia, trembling, Parkinson'sdisease, nerve impingements, Alzheimer's disease and Tourette'ssyndrome, among others.

In another particular embodiment, the cosmetic, non-therapeutictreatment and/or care of the skin, is a treatment and/or prevention,delay or hindering of aging and/or photoaging, treatment and/orprevention, delay or hindering of wrinkles and/or expression wrinkles,treatment and/or prevention, delay or hindering of perspiration,treatment and/or care of skin disorders selected, for example and notrestricted to, from the group formed by calluses and warts, amongothers. In an even more particular embodiment in its treatment and/orcare of the facial skin.

In another particular embodiment, the treatment and/or care of the hairis a hair-growth stimulating and/or hair loss prevention treatment.

In another particular embodiment, the treatment and/or prevention, delayor hindering of perspiration, and the treatment and/or prevention, delayor hindering of hyperhidrosis, are treatments and/or preventions, delayor hindering of perspiration or axillary, facial, genital, palmar orplantar hyperhidrosis.

In another aspect, the compounds of the invention can be administered byany means that causes contact between the compounds and the site ofaction in a mammal's body, preferably that of a human being, and in theform of a composition which contains them. The administration of thecompounds of this invention is carried out topically, transdermally,orally or parenterally. In a more particular aspect topical ortransdermal application is carried out by iontophoresis, sonophoresis,electroporation, mechanical pressure, osmotic pressure gradient,occlusive cure, microinjections, by needle-free injections by means ofpressure, by microelectric patches, face masks or any combinationthereof.

The frequency of the application can vary greatly, depending on theneeds of each subject, with a recommendation of an application from oncea month to ten times a day, preferably from once a week to four times aday, more preferably from three times a week to twice a day, even morepreferably once a day.

EXAMPLES OF ADMINISTRATION

The following specific examples provided here illustrate the nature ofthis invention. These examples are included for illustrative purposesonly and should not be construed as limitations on the invention claimedherein.

General Methodology

Abbreviations

The abbreviations used for amino acids follow the 1983 IUPAC-IUB JointCommission on Biochemical Nomenclature recommendations outlined in Eur.J. Biochem., (1984), 138, 9-37.

®, resin; 2,6-diCIZ, 2,6-dichlorobenzyl; 2-BrZ,2-bromobenzyloxycarbonyl; 2-ClTrt-®, 2-chlorotrityl resin; Ac, acetyl;Adpoc, 1-(1-adamantyl)-1-methylethoxy-carbonyl: Ala, alanine; All,allyl; Alloc, allyloxycarbonyl; AM,2-[4-aminomethyl-(2,4-dimethoxyphenyl)]phenoxyacetic acid; Arg,arginine; Asn, asparagine; Asp, aspartic acid; Boc,tert-butyloxycarbonyl; Bom, benzyloxymethyl; Brz,bromobenzyloxycarbonyl; BSA, bovine serum albumin; Bzl, benzyl; Cbz,benzyloxycarbonyl; cHx, cyclohexyl; ClZ, 2-chlorobenzyl; Cys, cysteine;C-terminal, carboxy-terminal; DCM, dichloromethane, methylene chloride;Dde, N-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl; DIEA,N,N′-diisopropylethylamine; DIPCDI, N,N′-diisopropylcarbodiimide; Dmab,4-(N-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]amino)benzyl;DMF, N,N-dimethylformamide; Dnp, 2,4-dinitrophenyl; EDTA,ethylenediaminetetraacetic acid; equiv, equivalent; ESI-MS, electrosprayionization mass spectrometry; Fm, fluorenylmethyl; Fmoc,9-fluorenylmethyloxycarbonyl; For, formyl; Gln, glutamine; Glu, glutamicacid; Gly, glycine; GST, glutathione S-transferase; His, histidine;HOAt, 1-hydroxyazabenzotriazole; HOBt, 1-hydroxybenzotriazole; HPLC,high performance liquid chromatography; Ile, isoleucine; INCI,International Nomenclature of Cosmetic Ingredients; IPL, Intense PulsedLight; ivDde, 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methyl-butyl;LDMA-25, lauryldimonium hydrolyzed protein; Leu, leucine; Lys, lysine;MBHA, p-methylbenzhydrylamine; Me, methyl; MeCN, acetonitrile; MeOH,methanol; Met, methionine; MetO, methionine(sulfoxide); MetO₂,methionine(sulfone); MLV, multilamellar vesicles; Mtr,4-methoxy-2,3,6-trimethylbenzenesulfonyl; Mts, mesitylenesulfonyl; Mtt,methoxytrityl or methyltrityl; Myr, myristoyl; MW, molecular weight;N-terminal, amino terminal; PAL,5-(4-aminomethyl-3,5-dimethoxyphenoxy)valeric acid; Palm, palmitoyl;Pbf, 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl; PEG,polyethylene glycol; Phe, phenylalanine; Pmc,2,2,5,7,8-pentamethylchroman-6-sulfonyl; pNZ, p-nitrobenzyloxycarbonyl;Pro, proline; q.s., quantity sufficient; q.s.p., quantity sufficientfor; SEM, standard error of the mean; Ser, serine; SNAP-25,synaptosomal-associated protein 25; SNARE, Soluble NSF AttachmentProtein Receptor; tBu, tert-butyl; Teoc,2-(trimethylsilyl)ethyloxycarbonyl; TFA, trifluoroacetic acid; THF,tetrahydrofuran; Thr, threonine; TIS, triisopropylsilane; Tos, tosyl orp-toluenesulfonyl; TPA, 12-O-tetradecanoylphorbol-13-acetate; Troc,2,2,2-trichloroethoxycarbonyl; Trp, tryptophan; Trt, triphenylmethyl ortrityl; Tyr, tyrosine; IUPAC, International Union of Pure and AppliedChemistry; IUB, International Union of Biochemistry; ULV, unilamellarvesicles; UVA, ultraviolet radiation A; UVB, ultraviolet radiation B;Val, valine; VAMP, vesicle-associated membrane proteins; Xan, xanthyl;Z, benzyloxycarbonyl.

Chemical Synthesis

All synthetic processes were carried out in polypropylene syringesfitted with porous polyethylene discs. All the reagents and solventswere synthesis quality and were used without any additional treatment.The solvents and soluble reagents were removed by suction. The Fmocgroup was removed with piperidine-DMF (2:8, v/v) (1×1 min, 1×5 min; 5mL/g resin) [Lloyd-Williams P. et al., “Chemical Approaches to theSynthesis of Peptides and Proteins”, (1997), CRC, Boca Raton (Fla.,USA)]. Washes between stages of deprotection, coupling, and, again,deprotection, were carried out with DMF (3×1 min) each time using 10 mLsolvent/g resin. The coupling reactions were performed with 3 mLsolvent/g resin. The control of the couplings was performed by carryingout the ninhydrin test [Kaiser E. et al., “Color test for detection offree terminal amino groups in the solid-phase synthesis of peptides”,(1970), Anal. Biochem., 34(2), 595-598] or chloranil test [ChristensenT., “A Qualitative Test for Monitoring Coupling Completeness in SolidPhase Peptide Synthesis Using Chloranil”, (1979), Acta Chem. Scand.,338, 763-766]. All synthetic reactions and washes were carried out at25° C.

The HPLC chromatographic analysis was carried out with a Shimadzuequipment (Kyoto, Japan) using a reversed-phase column thermostatized at30° C. (250×4.0 mm, Kromasil C₈, 5 μm, Akzo Nobel, Sweden). The elutionwas carried out using a gradient of acetonitrile (+0.07% TFA) in water(+0.1% TFA) at a flow rate of 1 mL/min and detection was carried out at220 nm. The electrospray ionization mass spectrometry was carried out ina WATERS Alliance ZQ 2000 detector using a mixture of MeCN:H₂O 4:1(+0.1% TFA) as the mobile phase and a flow rate of 0.2 mL/min.

Example 1

ObtainingFmoc-W_(n)—X_(m)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-AA₇-Y_(p)—Z_(q)-AM-MBHA-®,Wherein AA₁ is -L-Glu- or -L-Asp-; AA₂ is -L-Asn-, -L-Glu- or -L-Asp-;AA₃ is -L-Leu-, -L-Val- or -L-Met-; AA₄ is -L-Lys- or -L-his-; AA₅ is-L-Lys-, -L-his- or -L-Arg-; AA₆ is -L-Tyr- or -L-Trp-; AA₇ is -L-Met-or -L-MetO—; and n, m, p and q are 0.

5 mmol (1 equiv) of the Fmoc-AM-MBHA resin with a functionalization of0.73 mmol/g were treated with piperidine-DMF according to the describedgeneral protocol in order to remove the Fmoc group. 2.5 equiv ofFmoc-L-Met-OH or Fmoc-L-MetO—OH were incorporated onto the deprotectedresin in the presence of 2.5 equiv of DIPCDI and 2.5 equiv of HOBt,using DMF as a solvent, for 1 hour.

The resins were then washed as described in the general methods and thedeprotection treatment of the Fmoc group was repeated to couple the nextamino acid. The Fmoc N-terminal group was deprotected as described inthe general methods and 2.5 equiv of Fmoc-L-Tyr(tBu)-OH orFmoc-L-Trp(Boc)-OH; 2.5 equiv of Fmoc-L-Lys(Boc)-OH—, Fmoc-L-His(Trt)-OHor Fmoc-L-Arg(Pbf)-OH; 2.5 equiv of Fmoc-L-Lys(Boc)-OH— orFmoc-L-His(Trt)-OH; 2.5 equiv of Fmoc-L-Leu-OH, Fmoc-L-Val-OH orFmoc-L-Met-OH; 2.5 equiv of Fmoc-L-Asn(Trt)-OH, Fmoc-L-Glu(OtBu)-OH orFmoc-L-Asp(OtBu)-OH and finally 2.5 equiv of Fmoc-L-Glu(OtBu)-OH orFmoc-L-Asp(OtBu)-OH were sequentially coupled onto the peptidyl resinsfor 1 hour, each coupling in the presence of 2.5 equiv of HOBt and 2.5equiv of DIPCDI and using DMF as a solvent.

After the synthesis, the peptidyl resins were washed with DCM (5×3 min)and dried under nitrogen stream.

Example 2

Prophetic Synthesis ofFmoc-W_(n)—X_(m)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-AA₇-Y_(p)—Z_(q)—O-2-ClTrt-®,Wherein AA₁ is -L-Glu- or -L-Asp-; AA₂ is -L-Gln-, -L-Asn-, -L-Glu- or-L-Asp-; AA₃ is -L-Leu-, -L-Ile-, -L-Val-, -L-Met-, -L-MetO— or-L-MetO₂—; AA₄ is -L-Lys-, -L-his- or -L-Arg-; AA₅ is -L-Lys-, -L-his-or -L-Arg-; AA₆ is -L-Phe-, -L-Tyr- or -L-Trp-; AA₇ is -L-Met-, -L-MetO—or -L-MetO₂—; and n, m, p and q are 0.

8.8 mmol (1 equiv) of Fmoc-L-Met-OH, Fmoc-L-MetO—OH o Fmoc-L-MetO₂—OHdissolved in 55 mL of DCM to which 0.86 equiv of DIEA are added, arecoupled to the dry 2-chlorotrityl resin (5.5 g; 8.8 mmol). They arestirred for 5 min, after which 1.66 equiv of DIEA are added. The mixtureis allowed to react for 40 min. The remaining chloride groups areblocked by treatment with 4.4 mL of MeOH.

The N-terminal Fmoc group is deprotected as described in the generalmethods and 2.5 equiv of Fmoc-L-Phe-OH, Fmoc-L-Tyr(tBu)-OH orFmoc-L-Trp(Boc)-OH are coupled onto the peptidyl resins in presence of2.5 equiv of DIPCDI and 2.5 equiv of HOBt, using DMF as a solvent, for 1hour. The resins are then washed as described in the general methods andthe deprotection treatment of the Fmoc group is repeated to couple thenext amino acid. Following the protocols described, 2.5 equiv ofFmoc-L-Lys(Boc)-OH, Fmoc-L-His(Trt)-OH or Fmoc-L-Arg(Pbf)-OH; 2.5 equivof Fmoc-L-Lys(Boc)-OH, Fmoc-L-His(Trt)-OH or Fmoc-L-Arg(Pbf)-OH; 2.5equiv of Fmoc-L-Leu-OH, Fmoc-L-Ile-OH, Fmoc-L-Val-OH, Fmoc-L-Met-OH,Fmoc-L-MetO—OH or Fmoc-L-MetO₂—OH; 2.5 equiv of Fmoc-L-Gln(Trt)-OH,Fmoc-L-Asn(Trt)-OH, Fmoc-L-Glu(OtBu)-OH or Fmoc-L-Asp(OtBu)-OH andfinally 2.5 equiv of Fmoc-L-Glu(OtBu)-OH or Fmoc-L-Asp(OtBu)-OH aresequentially coupled in the presence of 2.5 equiv of HOBt and 2.5 equivof DIPCDI in each coupling.

After the synthesis, the peptidyl resins are washed with DCM (5×3 min)and dried under nitrogen stream.

Example 3

ObtainingFmoc-W_(n)—X_(m)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-AA₇-Y_(p)—Z_(q)-AM-MBHA-®,Wherein AA₁ is -L-Arg-, -L-Lys-, -L-Gln-, -L-Asn-, -L-Glu- or -L-Asp-;AA₂ is -L-his- or -L-Asp-; AA₃ is -L-Leu-, -L-Met- or -L-Phe-; AA₄ is-L-Lys-, -L-his-, -L-Gln- or -L-Leu-; AA₅ is -L-Arg-, -L-his-, -L-Lys-,-L-Gln-, -L-Asn-, -L-Glu- or -L-Asp-; AA₆ is -L-Tyr-, -L-Trp-, -L-Val-or -L-Arg-; AA₇ is -L-Met- or -L-MetO—; and n, m, p and q are 0.

5 mmol (1 equiv) of the Fmoc-AM-MBHA resin with a functionalization of0.73 mmol/g were treated with piperidine-DMF according to the describedgeneral protocol in order to remove the Fmoc group. 2.5 equiv ofFmoc-L-Met-OH or Fmoc-L-MetO—OH were incorporated onto the deprotectedresin in the presence of 2.5 equiv of DIPCDI and 2.5 equiv of HOBt,using DMF as a solvent, for 1 hour.

The resins were then washed as described in the general methods and thedeprotection treatment of the Fmoc group was repeated to couple the nextamino acid. The Fmoc N-terminal group was deprotected as described inthe general methods and 2.5 equiv of Fmoc-L-Tyr(tBu)-OH,Fmoc-L-Trp(Boc)-OH, Fmoc-L-Val-OH or Fmoc-L-Arg(Pbf)-OH; 2.5 equiv deFmoc-L-Arg(Pbf)-OH, Fmoc-L-His(Trt)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Gln(Trt)-OH, Fmoc-L-Asn(Trt)-OH, Fmoc-L-Glu(OtBu)-OH orFmoc-L-Asp(OtBu)-OH; 2.5 equiv of Fmoc-L-Lys(Boc)-OH—,Fmoc-L-His(Trt)-OH, Fmoc-L-Gln(Trt)-OH or Fmoc-L-Leu-OH; 2.5 equiv ofFmoc-L-Leu-OH, Fmoc-L-Met-OH or Fmoc-L-Phe-OH; 2.5 equiv ofFmoc-L-His(Trt)-OH or Fmoc-L-Asp(OtBu)-OH and finally 2.5 equiv ofFmoc-L-Arg(Pbf)-OH, Fmoc-L-Lys(Boc)-OH, Fmoc-L-Gln(Trt)-OH,Fmoc-L-Asn(Trt)-OH, Fmoc-L-Glu(OtBu)-OH or Fmoc-L-Asp(OtBu)-OH weresequentially coupled onto the peptidyl resins for 1 hour, each couplingin the presence of 2.5 equiv of HOBt and 2.5 equiv of DIPCDI and usingDMF as a solvent.

After the synthesis, the peptidyl resins were washed with DCM (5×3 min)and dried under nitrogen stream.

Example 4

Prophetic Synthesis ofFmoc-W_(n)—X_(m)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-AA₇-Y_(p)—Z_(q)—O-2-ClTrt-®,Wherein AA₁ is -L-Arg-, -L-his-, -L-Lys-, -L-Gln-, -L-Asn-, -L-Glu- or-L-Asp-; AA₂ is -L-his-, -L-Lys- or -L-Asp-; AA₃ is -L-Leu-, -L-Ile-,-L-Met-, -L-MetO—, -L-MetO₂—, -L-Phe- or -L-Tyr-; AA₄ is -L-Lys-,-L-his-, -L-Arg-, -L-Gln-, -L-Asn-, -L-Leu-, -L-Ile-, -L-Met-, -L-MetO—,-L-MetO₂— or -L-Val-; AA₅ is -L-Arg-, -L-his-, -L-Lys-, -L-Gln-,-L-Asn-, -L-Glu- or -L-Asp-; AA₆ is -L-Phe-, -L-Tyr-, -L-Trp-, -L-Met-,-L-MetO—, -L-MetO₂—, -L-Ile-, -L-Val-, -L-his-, -L-Lys- or -L-Arg-; AA₇is -L-Met-, -L-MetO— or -L-MetO₂—; and n, m, p and q are 0.

8.8 mmol (1 equiv) of Fmoc-L-Met-OH, Fmoc-L-MetO—OH or Fmoc-L-MetO₂—OHdissolved in 55 mL of DCM to which 0.86 equiv of DIEA are added, arecoupled to the dry 2-chlorotrityl resin (5.5 g; 8.8 mmol). They arestirred for 5 min, after which 1.66 equiv of DIEA are added. The mixtureis allowed to react for 40 min. The remaining chloride groups areblocked by treatment with 4.4 mL of MeOH.

The N-terminal Fmoc group is deprotected as described in the generalmethods and 2.5 equiv of Fmoc-L-Phe-OH, Fmoc-L-Tyr(tBu)-OH,Fmoc-L-Trp(Boc)-OH, Fmoc-L-Met-OH, Fmoc-L-MetO—OH, Fmoc-L-MetO₂—OH,Fmoc-L-Ile-OH, Fmoc-L-Val-OH, Fmoc-L-His(Trt)-OH, Fmoc-L-Lys(Boc)-OH orFmoc-L-Arg(Pbf)-OH are coupled onto the peptidyl resins in presence of2.5 equiv of DIPCDI and 2.5 equiv of HOBt, using DMF as a solvent, for 1hour. The resins are then washed as described in the general methods andthe deprotection treatment of the Fmoc group is repeated to couple thenext amino acid. Following the protocols described, 2.5 equiv ofFmoc-L-Arg(Pbf)-OH, Fmoc-L-His(Trt)-OH, Fmoc-L-Lys(Boc)-OH,Fmoc-L-Gln(Trt)-OH, Fmoc-L-Asn(Trt)-OH, Fmoc-L-Glu(OtBu)-OH orFmoc-L-Asp(OtBu)-OH; 2.5 equiv of Fmoc-L-Lys(Boc)-OH,Fmoc-L-His(Trt)-OH, Fmoc-L-Arg(Pbf)-OH, Fmoc-L-Gln(Trt)-OH,Fmoc-L-Asn(Trt)-OH, Fmoc-L-Leu-OH, Fmoc-L-Ile-OH, Fmoc-L-Met-OH,Fmoc-L-MetO—OH, Fmoc-L-MetO₂—OH or Fmoc-L-Val-OH; 2.5 equiv ofFmoc-L-Leu-OH, Fmoc-L-Ile-OH, Fmoc-L-Met-OH, Fmoc-L-MetO—OH,Fmoc-L-MetO₂—OH, Fmoc-L-Phe-OH or Fmoc-L-Tyr(tBu)-OH; 2.5 equiv ofFmoc-L-His(Trt)-OH, Fmoc-L-Lys(Boc)-OH or Fmoc-L-Asp(OtBu)-OH andfinally 2.5 equiv of Fmoc-L-Arg(Pbf)-OH, Fmoc-L-His(Trt)-OH,Fmoc-L-Lys(Boc)-OH, Fmoc-L-Gln(Trt)-OH, Fmoc-L-Asn(Trt)-OH,Fmoc-L-Glu(OtBu)-OH or Fmoc-L-Asp(OtBu)-OH are sequentially coupled inthe presence of 2.5 equiv of HOBt and 2.5 equiv of DIPCDI in eachcoupling.

After the synthesis, the peptidyl resins are washed with DCM (5×3 min)and dried under nitrogen stream.

Example 5

General Process for Cleavage of Fmoc N-Terminal Protective Group.

The N-terminal Fmoc group of the peptidyl resins obtained in examples 1and 3 was deprotected as described in the general methods (20%piperidine in DMF, 1×5 min+1×20 min). The peptidyl resins were washedwith DMF (5×1 min), DCM (4×1 min), diethyl ether (4×1 min) and driedunder vacuum.

Prophetically, using the same protocol the N-terminal Fmoc group of thepeptidyl resins obtained in examples 2 and 4 can be deprotected, washedand dried.

Example 6

Process for Introducing the R₁ Palmitoyl Group onto the Peptidyl ResinsObtained in Example 5 for SEQ ID NO:25.

10 equiv of palmitic acid pre-dissolved in DMF (1 mL) were added onto 1mmol (1 equiv) of the peptidyl resins obtained in Example 5 for SEQ IDNO:25, in the presence of 10 equiv of HOBt and 10 equiv of DIPCDI. Theywere allowed to react for 15 hours, after which the resins were washedwith THF (5×1 min), DCM (5×1 min), DMF (5×1 min), MeOH (5×1 min), DMF(5×1 min) THF (5×1 min), DMF (5×1 min), DCM (4×1 min), ether (3×1 min),and were dried under vacuum.

Prophetically, following the same protocol, the R₁ palmitoyl group canbe introduced onto the other peptidyl resins obtained in Examples 1 to 4after deprotecting the N-terminal following the protocol described inExample 5.

Example 7

Process for Introducing the R₁ Acetyl Group onto the Peptidyl ResinsObtained in Example 5.

1 mmol (1 equiv) of the peptidyl resins obtained in Example 5 wastreated with 25 equiv of acetic anhydride in the presence of 25 equiv ofDIEA, using 5 mL of DMF as a solvent. They were allowed to react for 30min, after which the peptide resins were washed with DMF (5×1 min), DCM(4×1 min), diethyl ether (4×1 min) and were dried under vacuum.

Prophetically, following the same protocol the R₁ acetyl group can beintroduced onto the peptidyl resins prophetically obtained in Examples5.

Example 8

Cleavage Process of the Peptidyl Resins Obtained in Examples 6 and 7from the Polymeric Support.

200 mg of the dried peptidyl resins obtained in Examples 6 and 7 weretreated with 5 mL of TFA:TIS:H₂O (90:5:5) for 2 hours at roomtemperature under stirring. The filtrates were collected onto 50 mL colddiethyl ether, filtered through polypropylene syringes fitted withporous polyethylene discs, and washed 5 times with 50 mL diethyl ether.The final precipitates were dried under vacuum.

HPLC analysis of the obtained peptides in gradients of MeCN (+0.07% TFA)in H₂O (+0.1% TFA) showed a purity exceeding 80% in all cases. Theidentity of the peptides obtained was confirmed by ESI-MS.

Prophetically, following the same protocol, the cleavage from thepolymeric support can be performed for the other peptidyl resinsprophetically obtained in Examples 5 to 7.

Example 9

Prophetic Cleavage Process from the Polymeric Support andFunctionalization with R₂ Substituted Amine: ObtainingAc—W_(n)—X_(m)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-AA₇-Y_(p)—Z_(q)—NH—(CH₂)₁₅—CH₃,Wherein AA₁ is -L-Glu- or -Asp-; AA₂ is -L-Gln-, -L-Asn-, -L-Glu- or-L-Asp-; AA₃ is -L-Leu-, -L-Ile-, -L-Val-, -L-Met-, -L-MetO—, -L-MetO₂—;AA₄ is -L-Lys-, -L-his- or -L-Arg-; AA₅ is -L-Lys-, -L-his- or -L-Arg-;AA₆ is -L-Phe-, -L-Tyr- or -L-Trp-; AA₇ is -L-Met-, -L-MetO— or-L-MetO₂—; and n, m, p and q are 0.

The compounds Ac—W_(n)—X_(m)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-AA₇-Y_(p)—Z_(q)—OHwith fully protected side chains are obtained by treating 150 mg of thepeptidyl resinsAc—W_(n)—X_(m)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-AA₇-Y_(p)—Z_(q)—O-2-ClTrt-® fromExample 7, previously desiccated under vacuum in the presence of KOH,with 3 mL of a 3% solution of TFA in DCM for 5 min. The filtrates arecollected onto 50 mL of cold diethyl ether and the treatment is repeatedthree times. The ether solutions are evaporated to dryness at reducedpressure and room temperature, the precipitates are redissolved in 50%of MeCN in H₂O and they are lyophilized. 10 mg of the obtained crudepeptides are weighed in a flask and 3 equiv of hexadecylamine and 25 mLof anhydrous DMF are added. 2 equiv of DIPCDI are added and allowed toreact under magnetic stirring at 47° C. The reactions are monitored byHPLC until disappearance of the initial products. The solvents areevaporated to dryness and co-evaporated twice with DCM. The obtainedresidues[Ac—W_(n)—X_(m)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-AA₇-Y_(p)—Z_(q)—NH—(CH₂)₁₅—CH₃with fully protected side chains] are redissolved in 25 mL of a mixtureof TFA-DCM-anisole (49:49:2) and allowed to react for 30 min at roomtemperature. 250 mL of cold diethyl ether are added, the solvents areevaporated under reduced pressure and two additional co-evaporationswith ether are carried out. The residues are dissolved in a mixture of50% MeCN in H₂O and lyophilized.

Purity of the obtained peptides is determined by HPLC analysis ingradients of MeCN (+0.07% TFA) in H₂O (+0.1% TFA). The identity of thepeptides obtained is confirmed by ESI-MS.

Example 10

Prophetic Cleavage Process from the Polymeric Support andFunctionalization with R₂ Substituted Amine: ObtainingAc—W_(n)—X_(m)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-AA₇-Y_(p)—Z_(q)—NH—(CH₂)₁₅—CH₃,Wherein AA₁ is -L-Arg-, -L-his-, -L-Lys-, -L-Gln-, -L-Asn-, -L-Glu- or-Asp-; AA₂ is -L-his-, -L-Lys- or -L-Asp-; AA₃ is -L-Leu-, -L-Ile-,-L-Met-, -L-MetO—, -L-MetO₂—, -L-Phe- or -L-Tyr-; AA₄ is -L-Lys-,-L-his-, -L-Arg-, -L-Gln-, -L-Asn-, -L-Leu-, -L-Ile-, -L-Met-, -L-MetO—,-L-MetO₂— or -L-Val-; AA₅ is -L-Arg-, -L-his-, -L-Lys-, -L-Gln-,-L-Asn-, -L-Glu- or -L-Asp-; AA₆ is -L-Phe-, -L-Tyr-, -L-Trp-, -L-Met-,-L-MetO—, -L-MetO₂—, -L-Ile-, -L-Val-, -L-his-, -L-Lys- or -L-Arg-; AA₇is -L-Met-, -L-MetO— or -L-MetO₂—; and n, m, p and q are 0.

The compounds Ac—W_(n)—X_(m)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-AA₇-Y_(p)—Z_(q)—OHwith fully protected side chains are obtained by treating 150 mg of theprophetic peptidyl resinsAc—W_(n)—X_(m)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-AA₇-Y_(p)—Z_(q)—O-2-ClTrt-® fromExample 7, previously desiccated under vacuum in the presence of KOH,with 3 mL of a 3% solution of TFA in DCM for 5 min. The filtrates arecollected onto 50 mL of cold diethyl ether and the treatment is repeatedthree times. The ether solutions are evaporated to dryness at reducedpressure and room temperature, the precipitates are redissolved in 50%of MeCN in H₂O and they are lyophilized. 10 mg of the obtained crudepeptides are weighed in a flask and 3 equiv of hexadecylamine and 25 mLof anhydrous DMF are added. 2 equiv of DIPCDI are added and allowed toreact under magnetic stirring at 47° C. The reactions are monitored byHPLC until disappearance of the initial products. The solvents areevaporated to dryness and co-evaporated twice with DCM. The obtainedresidues[Ac—W_(n)—X_(m)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-AA₇-Y_(p)—Z_(q)—NH—(CH₂)₁₅—CH₃with fully protected side chains] are redissolved in 25 mL of a mixtureof TFA-DCM-anisole (49:49:2) and allowed to react for 30 min at roomtemperature. 250 mL of cold diethyl ether are added, the solvents areevaporated under reduced pressure and two additional co-evaporationswith ether are carried out. The residues are dissolved in a mixture of50% MeCN in H₂O and lyophilized.

Purity of the obtained peptides can be determined by HPLC analysis ingradients of MeCN (+0.07% TFA) in H₂O (+0.1% TFA). The identity of thepeptides obtained can be confirmed by ESI-MS.

Example 11

Following the protocols described in examples 1 to 10, routinely varyingthe nature of the reagents and the peptide sequences, the followingcompounds included in the scope of this invention were also obtained.

TABLE 3 Identifier Average MW Experimental MW Ac-SEQ ID NO: 1-NH₂1012.20 1012.13 ± 0.11 Ac-SEQ ID NO: 2-NH₂ 1017.18 1017.88 ± 0.92 Ac-SEQID NO: 3-NH₂ 919.08  918.47 ± 0.83 Ac-SEQ ID NO: 8-NH₂ 1012.24 1012.52 ±0.29 Ac-SEQ ID NO: 9-NH₂ 999.16  999.19 ± 0.05 Ac-SEQ ID NO: 12-NH₂1012.20 1012.23 ± 0.05 Ac-SEQ ID NO: 13-NH₂ 1058.28 1057.81 ± 0.72Ac-SEQ ID NO: 14-NH₂ 1018.21 1018.08 ± 0.50 Ac-SEQ ID NO: 15-NH₂ 1002.161001.10 ± 1.88 Ac-SEQ ID NO: 16-NH₂ 1026.23 1026.40 ± 0.18 Ac-SEQ ID NO:21-NH₂ 1016.24 1016.10 ± 0.20 Ac-SEQ ID NO: 22-NH₂ 998.22  998.29 ± 0.15Ac-SEQ ID NO: 23-NH₂ 962.09  961.63 ± 0.68 Ac-SEQ ID NO: 24-NH₂ 1002.121002.13 ± 0.04 Ac-SEQ ID NO: 25-NH₂ 1004.13 1003.44 ± 0.78 Palm-SEQ IDNO: 25-NH₂ 1200.51 1200.55 ± 0.11 Ac-SEQ ID NO: 26-NH₂ 1017.18 1017.07 ±0.15 Ac-SEQ ID NO: 27-NH₂ 997.19  997.51 ± 0.55 Ac-SEQ ID NO: 30-NH₂1031.20 1031.22 ± 0.19 Ac-SEQ ID NO: 31-NH₂ 983.16  984.16 ± 1.01 Ac-SEQID NO: 32-NH₂ 1006.20 1006.23 ± 0.14 Ac-SEQ ID NO: 33-NH₂ 1058.281057.71 ± 0.72 Ac-SEQ ID NO: 34-NH₂ 1003.15 1001.52 ± 2.22 Ac-SEQ ID NO:50-NH₂ 1028.20 1028.14 ± 0.10 Ac-SEQ ID NO: 53-NH₂ 1034.20 1034.14 ±0.09 Ac-SEQ ID NO: 55-NH₂ 1018.12 1018.24 ± 0.49 Ac-SEQ ID NO: 56-NH₂1020.13 1020.59 ± 1.72 Ac-SEQ ID NO: 116-NH₂ 1032.23 1032.18 ± 0.12Ac-SEQ ID NO: 117-NH₂ 1017.22 1017.18 ± 0.07

Example 12

Study of the Inhibition of the SNARE Complex Formation with Detection ofthe Complex by ELISA

With the aim of determining the capacity of inhibition of the SNAREcomplex formation by the compounds of the invention, the competitiveinhibition of the compounds compared to SNAP-25 was studied with regardsto the formation of this complex. The proportion of SNARE complex formedwas determined by the ELISA technique, using one of the proteins fromthe complex bound to GST. In a 96-well plate VAMP was immobilized (usinga 0.037 μM solution) and subsequently the free spaces were blocked withBSA (3%). Parallel to this process, SNAP-25 bound to GST (0.0185 μM),syntaxin (0.037 μM) and a compound of the invention (2.5 mM and 0.5 mMcompounds) were incubated for 1 hour. After incubation, the samples weretransferred to the plate with immobilized VAMP and were incubated for 1hour to allow the formation of the SNARE complex. Afterward, the platewas washed and the complex was detected by a primary antibody anti-GST(Antibody anti-GST epitope TAG, Fisher Cat. no: PA1-982A). The readingwas carried out at a wavelength of 490 nm in a TECAN GENiosspectrophotometric reader.

Table 4 shows the results of the competitive inhibition of the formationof the SNARE complex by the compounds of the invention versus SNAP-25.The percentage of inhibition of the formation of the complex isinversely proportional to the quantity of SNARE complexspectrophotometrically detected.

TABLE 4 % inhibition formation SNARE complex Concentration of compoundCompound 2.5 mM 0.5 mM Ac-SEQ ID NO: 1-NH₂ 63 33 Ac-SEQ ID NO: 2-NH₂ 6426 Ac-SEQ ID NO: 3-NH₂ 64 31 Ac-SEQ ID NO: 8-NH₂ 44 11 Ac-SEQ ID NO:12-NH₂ 71 20 Ac-SEQ ID NO: 13-NH₂ 20 Not studied Ac-SEQ ID NO: 14-NH₂ 6743 Ac-SEQ ID NO: 15-NH₂ 42 48 Ac-SEQ ID NO: 22-NH₂ 72 18 Ac-SEQ ID NO:23-NH₂ 60 10 Ac-SEQ ID NO: 24-NH₂ 55 41 Ac-SEQ ID NO: 25-NH₂ 71 40Ac-SEQ ID NO: 27-NH₂ 14 Not studied Ac-SEQ ID NO: 30-NH₂ 71 24 Ac-SEQ IDNO: 31-NH₂ 59 26 Ac-SEQ ID NO: 32-NH₂ 19 Not studied Ac-SEQ ID NO:34-NH₂ 85 27 Ac-SEQ ID NO: 56-NH₂ Not studied 9 Ac-SEQ ID NO: 116-NH₂ 69Ac-SEQ ID NO: 117-NH₂ 65

Example 13

Study of the Inhibition of the SNARE Complex Formation with Detection ofthe Complex by Electrophoresis

VAMP (6 μM), syntaxin (6 μM) and the compound of the invention (5 mM or1 mM compounds) were incubated for 3 hours. Subsequently, SNAP-25 (0.6μM) was added and the mixture was incubated for an additional 15 hoursto allow the formation of the SNARE complex. After incubation, theloading buffer (Laemli Simple Buffer) was added and the mixture wasanalyzed by 10% acrylamide SDS-PAGE in gel. The amount of complex wasdetermined by MediaCybernetics image analysis software Image-Pro Plus.

Table 5 shows the results of the inhibition of the formation of theSNARE complex. The percentage of inhibition of the formation of thecomplex is inversely proportional to the quantity of SNARE complexdetected.

TABLE 5 % inhibition formation SNARE complex Concentration of compoundCompound 5 mM 1 mM Ac-SEQ ID NO: 1-NH₂ 100 59 Ac-SEQ ID NO: 2-NH₂ 80 37Ac-SEQ ID NO: 14-NH₂ 100 83 Ac-SEQ ID NO: 15-NH₂ 100 50 Ac-SEQ ID NO:24-NH₂ 100 48 Ac-SEQ ID NO: 25-NH₂ 100 83 Ac-SEQ ID NO: 34-NH₂ 59 14

Example 14

Quantification of the Release of Noradrenaline Induced by TPA/Ionomycinin a Neuroblastoma Cell Line by ELISA

The induction of the release of noradrenaline with TPA(12-O-tetradecanoylphorbol-13-acetate)/Ionomycin enables directmeasurement of neuronal exocytosis. For the study of the inhibitoryeffect of the compounds of the invention on the release ofnoradrenaline, cells of a human neuroblastoma cell line werepre-incubated (1×10⁶ cells/well) for 60 minutes with the compound of theinvention (1 μM, 10 μM, 100 μM, 500 μM or 1 mM compounds), and afterwardthe release of noradrenaline was induced. The release of thenoradrenaline neurotransmitter was induced by an 8 minute pre-treatmentwith a solution of 12-O-tetradecanoylphorbol-13-acetate (TPA) 100 nM,which mobilized the intracellular vesicles which contained theneurotransmitter; followed by a 5 minute incubation with TPA/Ionomycin(100 nM/10 μM), which induced the release of the neurotransmittercontained in these vesicles. The quantity of neurotransmitter releasedinto the growth medium was quantified by ELISA (Noradrenaline ELISA kit,IBL International ref. RE59261), in an assay mediated by specificantibodies against noradrenaline and completed by an enzymatic reactionbased on the reaction of alkaline phosphatase, which resulted in aquantifiable color indication. For this, absorbance at 405 nm wasmeasured in Thermo Scientific Multiskan Ascent equipment.

The blocking of the SNARE complex by the compounds of the invention leadto an inhibition of neuronal exocytosis and therefore, a decrease in thelevels of released noradrenaline (Table 6).

TABLE 6 % RELEASED NORADRENALINE TREATMENT DOSIS Average SEM TPA/ION100.00 3.11 Ac-SEQ ID NO: 1-NH₂   1 μM 96.14 5.61  10 μM 93.07 3.40  100μM 79.59 2.04  500 μM 49.08 1.49 1000 μM 42.48 0.89 Ac-SEQ ID NO: 24-  1 μM 90.63 2.38 NH₂  10 μM 97.06 1.76  100 μM 88.95 2.15  500 μM 78.112.92 1000 μM 67.90 2.79 Ac-SEQ ID NO: 25-   1 μM 99.59 1.81 NH₂  10 μM94.48 1.76  100 μM 74.79 3.66  500 μM 48.07 3.79 1000 μM 41.05 1.84Ac-SEQ ID NO: 14-  10 μM 84.96 7.24 NH₂  100 μM 85.97 8.38 1000 μM 45.782.08 Ac-SEQ ID NO: 116-   1 μM 87.59 4.72 NH₂  10 μM 83.30 4.58  100 μM62.24 3.53  500 μM 52.82 2.26 1000 μM 43.10 1.22 Ac-SEQ ID NO: 117-   1μM 87.99 5.20 NH₂  10 μM 83.11 4.82  100 μM 70.76 2.77  500 μM 58.372.82 1000 μM 54.64 3.53

Example 15

Preparation of a Cosmetic Facial Composition Containing Ac-SEQ IDNO:1-NH₂.

In a suitable vessel the components of phase A were dissolved. Next,carbomer was slowly added (INCI: CARBOMER) (phase A1), under stirring,until it was completely dissolved. The mixture was heated to 70-75° C.

In another vessel the components of phase B were mixed together and themixture was heated to 70-75° C.

Next the mixture of phase B was added to the aqueous solution of PhasesA+A1, stirred with a turbine to form an emulsion.

The compound Ac-SEQ ID NO:1-NH₂, ALDENINE® C (INCI: WATER (AQUA),HYDROLIZED SOY PROTEIN, HYDROLYZED WHEAT PROTEIN, XANTHAN GUM,TRIPEPTIDE-1), aqueous solution of LEUPHASYL® (INCI: WATER (AQUA),GLYCERIN, PENTAPEPTIDE-18, CAPRYLYL GLYCOL), SILICONE DC 200 (INCI:DIMETHICONE) and SILICONE DC 245 (INCI: CYCLOPENTASILOXANE) (phase C).were added stepwise under stirring to the previous emulsion at 40° C.until homogenization. Next, perfume (INCI: FRAGRANCE (PARFUM)) (phaseD), was slowly added under stirring until homogenized.

Finally, the pH of the mixture was adjusted to 5.5-7.0 with aqueoussolution of 20% sodium hydroxide.

TABLE 7 Cosmetic facial composition Phase INGREDIENT % in weight A WATER(AQUA) q.s.p. 100 A DISODIUM EDTA 0.30 A PHENONIP ® (INCI:PHENOXYETHANOL, METHYLPARABEN, ETHYLPARABEN, BUTYLPARABEN,PROPYLPARABEN, ISOBUTYLPARABEN): PHENOXYETHANOL, 0.610 METHYLPARABEN0.130 ETHYLPARABEN 0.033 BUTYLPARABEN 0.033 PROPYLPARABEN 0.017ISOBUTYLPARABEN 0.017 A IMIDAZOLIDINYL UREA 0.20 A GLYCERIN 3.00 A1CARBOMER 0.60 B MINERAL OIL (PARAFFINUM LIQUIDUM) 7.00 B BHT 0.05 BCETYL ALCOHOL 0.80 B BEESWAX (CERA ALBA) 0.50 B STEARYL ALCOHOL 1.50 BLIPOMULSE ® 165 (INCI: GLYCERYL STEARATE, PEG-100 STEARATE): GLYCERYLSTEARATE 1.25 PEG-100 STEARATE 1.25 B DIMETHYLMETHOXY CHROMANOL 0.01 BBENZOPHENONE-3 0.20 B ETHYLHEXYL METHOXYCINNAMATE 0.90 B CETEARYLALCOHOL 1.00 C Ac-SEQ ID NO: 1-NH₂ 0.10 C ALDENINE ® C (INCI: WATER(AQUA), HYDROLIZED SOY PROTEIN, HYDROLYZED WHEAT PROTEIN, XANTHAN GUM,TRIPEPTIDE-1): WATER (AQUA) 1.195 HYDROLIZED SOY PROTEIN 0.500HYDROLYZED WHEAT PROTEIN 0.300 XANTHAN GUM 0.003 TRIPEPTIDE-1 0.002 CLEUPHASYL ® SOLUTION (INCI: WATER (AQUA), GLYCERIN, PENTAPEPTIDE-18,CAPRYLYL GLYCOL): WATER (AQUA) 4.473 GLYCERIN 0.500 PENTAPETIDE-18 0.003CAPRYLYL GLYCOL 0.024 C DIMETHICONE 0.10 C CYCLOPENTASILOXANE 1.00 DFRAGRANCE (PARFUM) 0.05 E 20% SODIUM HYDROXIDE q.s.p. pH 5.5-7

Example 16

Prophetic Preparation of a Cosmetic Facial Composition Containing Ac-SEQID NO:24-NH₂

In a suitable vessel the components from phase A are dissolved and themixture is heated to 70-75° C.

Next the mixture of phase B is added to the aqueous solution of Phase Aunder turbine stirring to form an emulsion. The emulsion is heated to40° C. and the compound Ac-SEQ ID NO:24-NH₂, aqueous solution ofARGIRELINE® (INCI: WATER (AQUA), ACETYL HEXAPEPTIDE-8) and ANTARCTICINE®(INCI: WATER (AQUA), PSEUDOALTEROMONAS FERMENT EXTRACT) (phase C) isadded under stirring. Finally, the perfume (INCI: FRAGRANCE (PARFUM))(phase D) is added.

TABLE 8 Cosmetic facial composition Phase INGREDIENT % in weight A WATER(AQUA) q.s.p. 100 A GLYCERIN 3.00 A MAGNESIUM SULFATE 1.00 A PHENONIP ®(INCI: PHENOXYETHANOL, METHYLPARABEN, ETHYLPARABEN, BUTYLPARABEN,PROPYLPARABEN, ISOBUTYLPARABEN): PHENOXYETANOL 0.363 METHYLPARABEN 0.077ETHYLPARABEN 0.020 BUTYLPARABEN 0.020 PROPYLPARABEN 0.010ISOBUTYLPARABEN 0.010 A DISODIUM EDTA 0.15 A IMIDAZOLIDINYL UREA 0.1 BMINERAL OIL (PARAFFINUM LIQUIDUM) 10.00 B ETHYLHEXYL COCOATE 10.00 BCETYL PEG/PPG-10/1 DIMETHICONE 2.00 B BEESWAX (CERA ALBA) 1.50 BHYDROGENATED CASTOR OIL 1.00 B TOCOPHERYL ACETATE 0.10 C Ac-SEQ ID NO:24-NH₂ 0.10 C ARGIRELINE ® SOLUTION (INCI: WATER (AQUA), ACETYLHEXAPEPTIDE-8): WATER (AQUA) 9.995 ACETYL HEXAPEPTIDE-8 0.005 CANTARCTICINE ® (INCI: WATER (AQUA), PSEUDOALTEROMONAS FERMENT EXTRACT):WATER (AQUA) 3.750 PSEUDOALTEROMONAS FERMENT 1.250 EXTRACT D FRAGRANCE(PARFUM) 0.10

Example 17

Prophetic Preparation of a Face Cream Containing Ac-SEQ ID NO:25-NH₂.

In a suitable vessel pentylene glycol [INCI: PENTYLENE GLYCOL], benzylalcohol [INCI: BENZYL ALCOHOL], INYLINE™ [INCI: ACETYL HEXAPEPTIDE-30]and the compound Ac-SEQ ID NO:25-NH₂ (phase A) are dissolved in waterunder constant, light stirring. Once homogenized, carbomer [INCI:CARBOMER] (phase A1) is added and the mixture is stirred untilcompletely dissolved. Next, potassium cetyl phosphate [INCI: POTASSIUMCETYL PHOSPHATE] (phase A2) is added until it is dispersed and the wholemixture is heated to 70-75° C.

In a separate vessel the components of phase B are mixed together,heated to 70-75° C. and, once homogenized, phase B is added little bylittle to phase A under constant stirring.

With the mixture at about 50° C., phase C is slowly added maintainingstirring. Phase D is then added until homogenization.

Once the mixture is homogenized, the pH is adjusted to 6.0-6.5 withphase E. Finally, the perfume is added (phase F).

TABLE 9 Face cream composition Phase INGREDIENT % in weight A WATER(AQUA) q.s.p. 100 A PENTYLENE GLYCOL 5.0 A BENZYL ALCOHOL 0.40 A Ac-SEQID NO: 25-NH₂ 0.10 A ACETYL HEXAPEPTIDE-30 0.05 A1 CARBOMER 0.50 A2POTASSIUM CETYL PHOSPHATE 0.50 B SOYBEAN (GLYCINE SOJA) OIL 5.00 BPHYTOCREAM 2000 ® (INCI: GLYCERYL STEARATE, CETEARYL ALCOHOL, POTASSIUMPALMITOYL HYDROLYZED WHEAT PROTEIN): GLYCERYL STEARATE 2.050 CETEARYLALCOHOL 2.050 POTASSIUM PALMITOYL HYDROLYZED WHEAT 0.900 PROTEIN BETHYLHEXYL COCOATE 2.00 B PHENOXYETHANOL 0.90 C DIMETHICONE 1.00 DSEPIGEL ™ 305 (INCI: POLYACRYLAMIDE, WATER (AQUA), C13-14 ISOPARAFFIN,LAURETH-7) POLYACRYLAMIDE 0.400 WATER (AQUA) 0.340 C13-14 ISOPARAFFIN0.200 LAURETH-7 0.060 E 20% SODIUM HYDROXIDE q.s.p. pH 6.0-6.5 FFRAGRANCE (PARFUM) 0.20

Example 18

Preparation of an Antiperspirant Serum Containing Ac-SEQ ID NO:14-NH₂.

In a suitable vessel Phase B was stirred until it dissolved. In anothervessel, the ingredients from phase C were heated until completelydissolved, and phase C was added, under stirring, to phase B.

In a separate vessel the compound Ac-SEQ ID NO:14-NH₂ and PHENONIP®[INCI: PHENOXYETHANOL, METHYLPARABEN, ETHYLPARABEN, BUTYLPARABEN,PROPYLPARABEN, ISOBUTYLPARABEN] (phase A) were dissolved in water, understirring.

Finally, phase A was added to the mixture of phases B+C, under stirringuntil homogenized.

TABLE 10 Antiperspirant serum composition Phase INGREDIENT % in weight AWATER (AQUA) 0.50 A Ac-SEQ ID NO: 14-NH₂ 0.50 A PHENONIP ® (INCI:PHENOXYETHANOL, METHYLPARABEN, ETHYLPARABEN, BUTYLPARABEN,PROPYLPARABEN, ISOBUTYLPARABEN): PHENOXYETHANOL 0.36 METHYLPARABEN 0.08ETHYLPARABEN 0.02 BUTYLPARABEN 0.02 PROPYLPARABEN 0.01 ISOBUTYLPARABEN0.01 B SILICONE 9040 (INCI: CYCLOPENTASILOXANE, DIMETHICONECROSSPOLYMER): CYCLOPENTASILOXANE 43.265 DIMETHICONE CROSSPOLYMER 7.635CYCLOPENTASILOXANE 31.36 B FRAGRANCE (PARFUM) 0.13 C ETHYLHEXYL COCOATE12.43 C C24-28 ALKYL DIMETHICONE 2.25 C LECITHIN 1.38 C BHT 0.05

Example 19

Preparation of a Cosmetic Facial Composition Containing Ac-SEQ IDNO:116-NH₂.

In a suitable vessel the components of phase A were dissolved. Next,carbomer was slowly added (INCI: CARBOMER) (phase A1), under stirring,until it was completely dissolved. The mixture was heated to 70-75° C.

In another vessel the components of phase B were mixed together and themixture was heated to 70-75° C.

Next the mixture of phase B was added to the aqueous solution of PhasesA+A1, stirred with a turbine to form an emulsion.

The compound Ac-SEQ ID NO:116-NH₂, ALDENINE® C (INCI: WATER (AQUA),HYDROLIZED SOY PROTEIN, HYDROLYZED WHEAT PROTEIN, XANTHAN GUM,TRIPEPTIDE-1), aqueous solution of LEUPHASYL® (INCI: WATER (AQUA),GLYCERIN, PENTAPEPTIDE-18, CAPRYLYL GLYCOL), SILICONE DC 200 (INCI:DIMETHICONE) and SILICONE DC 245 (INCI: CYCLOPENTASILOXANE) (phase C).were added stepwise under stirring to the previous emulsion at 40° C.until homogenization. Next, perfume (INCI: FRAGRANCE (PARFUM)) (phaseD), was slowly added under stirring until homogenized.

Finally, the pH of the mixture was adjusted to 5.5-7.0 with aqueoussolution of 20% sodium hydroxide.

TABLE 11 Cosmetic facial composition Phase INGREDIENT % in weight AWATER (AQUA) q.s.p. 100 A DISODIUM EDTA 0.30 A PHENONIP ® (INCI:PHENOXYETHANOL, METHYLPARABEN, ETHYLPARABEN, BUTYLPARABEN,PROPYLPARABEN, ISOBUTYLPARABEN): PHENOXYETHANOL, 0.610 METHYLPARABEN0.130 ETHYLPARABEN 0.033 BUTYLPARABEN 0.033 PROPYLPARABEN 0.017ISOBUTYLPARABEN 0.017 A IMIDAZOLIDINYL UREA 0.20 A GLYCERIN 3.00 A1CARBOMER 0.60 B MINERAL OIL (PARAFFINUM LIQUIDUM) 7.00 B BHT 0.05 BCETYL ALCOHOL 0.80 B BEESWAX (CERA ALBA) 0.50 B STEARYL ALCOHOL 1.50 BLIPOMULSE ® 165 (INCI: GLYCERYL STEARATE, PEG-100 STEARATE): GLYCERYLSTEARATE 1.25 PEG-100 STEARATE 1.25 B DIMETHYLMETHOXY CHROMANOL 0.01 BBENZOPHENONE-3 0.20 B ETHYLHEXYL METHOXYCINNAMATE 0.90 B CETEARYLALCOHOL 1.00 C Ac-SEQ ID NO: 116-NH₂ 0.10 C ALDENINE ® C (INCI: WATER(AQUA), HYDROLIZED SOY PROTEIN, HYDROLYZED WHEAT PROTEIN, XANTHAN GUM,TRIPEPTIDE-1): WATER (AQUA) 1.195 HYDROLIZED SOY PROTEIN 0.500HYDROLYZED WHEAT PROTEIN 0.300 XANTHAN GUM 0.003 TRIPEPTIDE-1 0.002 CLEUPHASYL ® SOLUTION (INCI: WATER (AQUA), GLYCERIN, PENTAPEPTIDE-18,CAPRYLYL GLYCOL): WATER (AQUA) 4.473 GLYCERIN 0.500 PENTAPETIDE-18 0.003CAPRYLYL GLYCOL 0.024 C DIMETHICONE 0.10 C CYCLOPENTASILOXANE 1.00 DFRAGRANCE (PARFUM) 0.05 E 20% SODIUM HYDROXIDE q.s.p. pH 5.5-7

Example 20

Preparation of a Cosmetic Facial Composition Containing Ac-SEQ IDNO:14-NH₂.

In a suitable vessel the components from phase A were dissolved and themixture was heated to 70-75° C.

Next the mixture of phase B was added to the aqueous solution of Phase Aunder turbine stirring to form an emulsion. The emulsion was heated to40° C. and the compound Ac-SEQ ID NO:14-NH₂, aqueous solution ofARGIRELINE® (INCI: WATER (AQUA), ACETYL HEXAPEPTIDE-8) and ANTARCTICINE®(INCI: WATER (AQUA), PSEUDOALTEROMONAS FERMENT EXTRACT) (phase C) wereadded under stirring. Finally, the perfume (INCI: FRAGRANCE (PARFUM))(phase D) was added.

TABLE 12 Cosmetic facial composition Phase INGREDIENT % in weight AWATER (AQUA) q.s.p. 100 A GLYCERIN 3.00 A MAGNESIUM SULFATE 1.00 APHENONIP ® (INCI: PHENOXYETHANOL, METHYLPARABEN, ETHYLPARABEN,BUTYLPARABEN, PROPYLPARABEN, ISOBUTYLPARABEN): PHENOXYETANOL 0.363METHYLPARABEN 0.077 ETHYLPARABEN 0.020 BUTYLPARABEN 0.020 PROPYLPARABEN0.010 ISOBUTYLPARABEN 0.010 A DISODIUM EDTA 0.15 A IMIDAZOLIDINYL UREA0.1 B MINERAL OIL (PARAFFINUM LIQUIDUM) 10.00 B ETHYLHEXYL COCOATE 10.00B CETYL PEG/PPG-10/1 DIMETHICONE 2.00 B BEESWAX (CERA ALBA) 1.50 BHYDROGENATED CASTOR OIL 1.00 B TOCOPHERYL ACETATE 0.10 C Ac-SEQ ID NO:14-NH₂ 0.10 C ARGIRELINE ® SOLUTION (INCI: WATER (AQUA), ACETYLHEXAPEPTIDE-8): WATER (AQUA) 9.995 ACETYL HEXAPEPTIDE-8 0.005 CANTARCTICINE ® (INCI: WATER (AQUA), PSEUDOALTEROMONAS FERMENT EXTRACT):WATER (AQUA) 3.750 PSEUDOALTEROMONAS FERMENT 1.250 EXTRACT D FRAGRANCE(PARFUM) 0.10

Example 21

Preparation of a Face Cream Containing Ac-SEQ ID NO:117-NH₂.

In a suitable vessel pentylene glycol [INCI: PENTYLENE GLYCOL], benzylalcohol [INCI: BENZYL ALCOHOL], INYLINE™ [INCI: ACETYL HEXAPEPTIDE-30]and the compound Ac-SEQ ID NO:117-NH₂ (phase A) were dissolved in waterunder constant, light stirring. Once homogenized, carbomer [INCI:CARBOMER] (phase A1) was added and the mixture was stirred untilcompletely dissolved. Next, potassium cetyl phosphate [INCI: POTASSIUMCETYL PHOSPHATE] (phase A2) was added until it was dispersed and thewhole mixture was heated to 70-75° C.

In a separate vessel the components of phase B were mixed together,heated to 70-75° C. and, once homogenized, phase B was added little bylittle to phase A under constant stirring.

With the mixture at about 50° C., phase C was slowly added maintainingstirring. Phase D was then added until homogenization.

Once the mixture was homogenized, the pH was adjusted to 6.0-6.5 withphase E. Finally, the perfume was added (phase F).

TABLE 13 Face cream composition Phase INGREDIENT % in weight A WATER(AQUA) q.s.p. 100 A PENTYLENE GLYCOL 5.0 A BENZYL ALCOHOL 0.40 A Ac-SEQID NO: 117-NH₂ 0.10 A ACETYL HEXAPEPTIDE-30 0.05 A1 CARBOMER 0.50 A2POTASSIUM CETYL PHOSPHATE 0.50 B SOYBEAN (GLYCINE SOJA) OIL 5.00 BPHYTOCREAM 2000 ® (INCI: GLYCERYL STEARATE, CETEARYL ALCOHOL, POTASSIUMPALMITOYL HYDROLYZED WHEAT PROTEIN): GLYCERYL STEARATE 2.050 CETEARYLALCOHOL 2.050 POTASSIUM PALMITOYL HYDROLYZED 0.900 WHEAT PROTEIN BETHYLHEXYL COCOATE 2.00 B PHENOXYETHANOL 0.90 C DIMETHICONE 1.00 DSEPIGEL ™ 305 (INCI: POLYACRYLAMIDE, WATER (AQUA), C13-14 ISOPARAFFIN,LAURETH-7) POLYACRYLAMIDE 0.400 WATER (AQUA) 0.340 C13-14 ISOPARAFFIN0.200 LAURETH-7 0.060 E 20% SODIUM HYDROXIDE q.s.p. pH 6.0-6.5 FFRAGRANCE (PARFUM) 0.20

Example 22

Prophetic Preparation of a Face Cream Containing Palm-SEQ ID NO:1-NH₂.

In a suitable vessel pentylene glycol (PENTYLENE GLYCOL), benzyl alcohol(INCI: BENZYL ALCOHOL), glycerol (INCI: GLYCEROL), urea (INCI: UREA) andthe compound Palm-SEQ ID NO:1-NH₂ (phase A) are dissolved in water.Next, carbomer (INCI: CARBOMER) (phase A1) is slowly added, understirring, until it is completely dissolved. The mixture is heated to70-75° C.

The mixture of phase B is added to the aqueous solution of Phases A+A1under turbine stirring to form an emulsion.

The perfume (INCI: FRAGRANCE (PARFUM)) (phase C) is added to theprevious emulsion at 40° C.

Finally, the pH of the mixture is adjusted to 6.0-6.5 with aqueoussolution of 20% sodium hydroxide when required.

TABLE 14 Face cream composition Phase INGREDIENT % in weight A WATER(AQUA) q.s.p. 100 A PENTYLENE GLYCOL 5.0 A BENZYL ALCOHOL 0.40 AGLYCERIN 1.00 A UREA 1.00 A Palm-SEQ ID NO: 1-NH₂ 0.10 A1 CARBOMER 0.60B LIPOMULSE ® 165 (INCI: GLYCERYL STEARATE, PEG-100 STEARATE): GLYCERYLSTEARATE 1.500 PEG-100 STEARATE 1.500 B CETEARETH-25 2.00 B SHEA BUTTER(BUTYROSPERMUM PARKII) 2.00 B CAPRYLIC/CAPRIC TRIGLYCERIDE 1.00 BETHYLHEXYL COCOATE 7.00 B PHENOXYETHANOL 0.90 B DIMETHICONE 1.00 CFRAGRANCE (PARFUM) 0.20 D 20% SODIUM HYDROXIDE q.s.p. pH 6.0-6.5

Example 23

Preparation of Liposomes Containing Ac-SEQ ID NO:116-NH₂.

Dipalmitoylphosphatidylcholine (DPPC) was weighed and dissolved inchloroform. The solvent was evaporated to dryness until a fine layer ofphospholipid was obtained, and this layer was hydrated by treatment withan aqueous solution which contained the peptide Ac-SEQ ID NO:116-NH₂ atthe desired concentration (containing PHENONIP®) at 55° C., obtainingthe MLV liposomes. The ULV liposomes were obtained by submerging the MLVliposomes in an ultrasound bath at 55° C. for 8 cycles of 2 minutes atintervals of 5 minutes.

TABLE 15 INGREDIENT % IN WEIGHT WATER (AQUA) q.s.p. 100DIPALMITOYLPHOSPHATIDYLCHOLINE 4.00 Ac-SEQ ID NO: 116-NH₂ 0.20PHENONIP ® (INCI: PHENOXYETHANOL, METHYLPARABEN, ETHYLPARABEN,BUTYLPARABEN, PROPYLPARABEN, ISOBUTYLPARABEN): ISOBUTYLPARABEN 0.01PHENOXYETHANOL 0.36 METHYLPARABEN 0.08 ETHYLPARABEN 0.02 BUTYLPARABEN0.02 PROPYLPARABEN 0.01

Example 24

Preparation of Coacervation Capsules Containing the Compound Palm-SEQ IDNO:25-NH₂

a) Preparation of an Emulsion of the Compound Palm-SEQ ID NO:25-NH₂

In a suitable vessel the peptide was dissolved in water (phase A)heating the mixture to 70° C. In a separate vessel soybean oil [INCI:SOYBEAN (GLYCINE SOJA) OIL], Abil EM 90 [INCI: CETYL PEG/PPG-10/1DIMETHICONE] and Span 65 [INCI: SORBITAN TRISTEARATE] (phase B) weremixed together, heating the mixture to 80° C. until the Span 65dissolved. Once melted, phase A was added to phase B slowly underintense stirring with a turbine. Once the components were mixedtogether, the mixture was stirred until it reached room temperature.

TABLE 16 Phase INGREDIENT % in weight A PURIFIED WATER 56.00 B SOYBEAN(GLYCINE SOJA) OIL 33.00 B CETYL PEG/PPG-10/1 DIMETHICONE 5.00 BSORBITAN TRISTEARATE 4.00 A Palm-SEQ ID NO: 25-NH₂ 2.00b) Preparation of a Microfluidized Emulsion of the Compound Palm-SEQ IDNO:25-NH₂

The components of phase A were mixed together in water: ZemeaPropanediol [INCI: PROPANEDIOL], phenoxyethanol [INCI: PHENOXYETHANOL],Structure XL [INCI: HYDROXYPROPYL STARCH PHOSPHATE], Amigel [INCI:SCLEROTIUM GUM] and powdered hyaluronic acid [INCI: SODIUM HYALURONATE],the mixture was heated to 70° C. under stirring. In another vessel, theemulsion from section a), and the components of phase B: Massocare HD[INCI: ISOHEXADECANE], Arlacel [INCI: SORBITAN SESQUIOLEATE],LIPOCHROMAN™ [INCI: DIMETHYLMETHOXY CHROMANOL] were mixed together, andthe mixture was heated to 80° C. under stirring.

Once this temperature was reached, phase B was added to phase A veryslowly under intense stirring with a turbine.

The sample was passed, without cooling, through a microfluidizer forthree cycles at an entrance pressure of 80 bar and an exit pressure of15000 psi, maintaining the operating temperature between 65 and 75° C.Once microfluidized, the emulsion was stirred with a rotor until roomtemperature was reached.

TABLE 17 Phase INGREDIENT % in weight A WATER (AQUA) 70.36 B Emulsionsection a) 10.95 B ISOHEXADECANE 5.48 A PROPANEDIOL 5.48 B SORBITANSESQUIOLEATE 4.38 A PHENOXYETHANOL 2.85 A HYDROXYPROPYL STARCH PHOSPHATE0.33 A SCLEROTIUM GUM 0.11 B DIMETHYLMETHOXY CHROMANOL 0.05 A SODIUMHYALURONATE 0.01c) Obtaining Coacervate Capsules Containing the Compound Palm-SEQ IDNO:25-NH₂

In a vessel the emulsion from section b) (phase A) was weighed. Inanother vessel Sensomer CI 50 [INCI: WATER (AQUA); STARCHHYDROXYPROPYLTRIMONIUM CHLORIDE; UREA; SODIUM LACTATE; SODIUM CHLORIDE;SODIUM BENZOATE] was dissolved in water (phase B). Phase B was added tophase A under intense stirring.

Amigel [INCI: SCLEROTIUM GUM] (phase C) was added to the previousmixture very slowly and under intense stirring. The mixture was stirredfor 2 hours to obtain good hydration of the gum.

Next, Structure XL [INCI: HYDROXYPROPYL STARCH PHOSPHATE] (phase D) wasadded, maintaining the stirring for another hour to obtain the completehydration of the biopolymers added.

Finally, Sepigel™ 305 [INCI: POLYACRYLAMIDE; WATER (AQUA); C13-14ISOPARAFFIN; LAURETH-7] (phase E) was added, maintaining the stirringuntil a homogenous suspension was obtained. The average size of thecapsules in suspension obtained determined by Dynamic Laser LightScattering was approximately 300 nm.

TABLE 18 Phase INGREDIENT % in weight A Emulsion section b) 91.30 BWATER (AQUA) 6.00 D HYDROXYPROPYL STARCH PHOSPHATE 1.50 C SCLEROTIUM GUM0.75 E SEPIGEL ™ 305 (INCI: POLYACRYLAMIDE, WATER (AQUA), C13-14ISOPARAFFIN, LAURETH-7): POLYACRYLAMIDE 0.10 WATER (AQUA) 0.085 C13-14ISOPARAFFIN 0.05 LAURETH-7 0.015 B SENSOMER CI 50 [INCI: WATER (AQUA);STARCH HYDROXYPROPYLTRIMONIUM CHLORIDE; UREA; SODIUM LACTATE; SODIUMCHLORIDE; SODIUM BENZOATE]: WATER (AQUA) 0.137 STARCHHYDROXYPROPYLTRIMONIUM 0.048 CHLORIDE UREA 0.006 SODIUM LACTATE 0.004SODIUM CHLORIDE 0.004 SODIUM BENZOATE 0.001

The Sequence listing entitled 788774_1.txt filed herewith isincorporated by reference herein in its entirety.

It will be appreciated that variants of the above-disclosed and otherfeatures and functions, or alternatives thereof, may be combined intomany other different systems or applications. Various presentlyunforeseen or unanticipated alternatives, modifications, variations orimprovements therein may be subsequently made by those skilled in theart which are also intended to be encompassed by the following claims.

The invention claimed is:
 1. A compound of general formula (I):R₁—X_(m)-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-AA₇-Y_(p)—Z_(q)—R₂  (I) itsstereoisomers, mixtures thereof and/or its cosmetically orpharmaceutically acceptable salts, wherein: AA₁ is selected from thegroup consisting of -Arg-, -Lys-, -Gln-, -Asn-, -Glu- and -Asp-; AA₂ isselected from the group consisting of -His-, -Gln-, -Asn-, -Glu- and-Asp-; AA₃ is selected from the group consisting of -Leu- and -Phe-; AA₄is selected from the group consisting of -Lys-, -His-, -Gln-, and -Leu-;AA₅ is selected from the group consisting of -Arg-, -His-, -Lys-, -Gln-,-Asn-, -Glu- and -Asp-; AA₆ is selected from the group consisting of-Trp- and -Val-; AA₇ is selected from the group consisting of -Met-,-MetO— and -MetO₂—; X, Y, and Z are amino acids and are independentlyselected from amongst themselves; m, p and q are independently selectedfrom amongst themselves and have a value of 0 or 1; m+p+q is smallerthan or equal to 2; R₁ is selected from the group consisting of H, apolymer derived from polyethylene glycol, a non-cyclic substituted orunsubstituted aliphatic group, substituted or unsubstituted alicyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedheteroarylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted aralkyl and R₅—CO—, wherein R₅ is selected from the groupconsisting of H, a non-cyclic substituted or unsubstituted aliphaticgroup, substituted or unsubstituted alicyclyl, substituted orunsubstituted aryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heterocyclyl and substituted or unsubstitutedheteroarylalkyl; R₂ is selected from the group consisting of —NR₃R₄,—OR₃ and —SR₃, wherein R₃ and R₄ are independently selected from thegroup consisting of H, a polymer derived from polyethylene glycol, anon-cyclic substituted or unsubstituted aliphatic group, substituted orunsubstituted alicyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted heteroarylalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted aralkyl; wherein atleast one of: R₁ is not H, and R₂ is not OH; and R₁ and R₂ are notα-amino acids.
 2. The compound according to claim 1, wherein AA₄ isselected from the group consisting of -Lys- and -Leu-, and AA₆ is -Trp-.3. The compound according to claim 2, wherein m, p and q are
 0. 4. Thecompound according to claim 1, wherein R₁ is selected from the groupconsisting of H, acetyl, lauroyl, myristoyl and palmitoyl, AA₁ is-L-Glu-, AA₂ is selected from the group consisting of -L-Asn-, -L-Glu-,-L-Gln- and -L-Asp-, AA₃ is -L-Leu-, AA₄ is -L-Lys-, AA₅ is -L-Arg-, AA₆is -L-Trp-, AA₇ is selected from the group consisting of -L-Met-,-L-MetO— and -L-MetO₂—, and R₂ is selected from the group consisting of—NR₃R₄ and —OR₃ where R₃ and R₄ are independently selected from H,methyl, ethyl, hexyl, dodecyl and hexadecyl.
 5. A cosmetic orpharmaceutical composition which comprises at least one compound ofgeneral formula (I), its stereoisomers, mixtures thereof and/or itscosmetically or pharmaceutically acceptable salts, according to claim 1,together with at least one cosmetically or pharmaceutically acceptableexcipient or adjuvant.
 6. The composition according to claim 5, whereinthis compound of general formula (I), its stereoisomers, mixturesthereof and/or its cosmetically or pharmaceutically acceptable salts, isincorporated into a cosmetically or pharmaceutically acceptable deliverysystem or sustained release system selected from the group consisting ofliposomes, mixed liposomes, oleosomes, niosomes, ethosomes,milliparticles, microparticles, nanoparticles, solid lipidnanoparticles, nanostructured lipid carriers, sponges, cyclodextrins,vesicles, micelles, mixed micelles of surfactants,surfactant-phospholipid mixed micelles, millispheres, microspheres,nanospheres, lipospheres, millicapsules, microcapsules, nanocapsules,microemulsions and nanoemulsions or is adsorbed on a solid organicpolymer or solid mineral support selected from the group consisting oftalc, bentonite, silica, starch and maltodextrin.
 7. The compositionaccording to claim 5, wherein this composition is presented in aformulation selected from the group consisting of creams, multipleemulsions, anhydrous compositions, aqueous dispersions, oils, milks,balsams, foams, lotions, gels, cream gels, hydroalcoholic solutions,hydroglycolic solutions, hydrogels, liniments, sera, soaps, shampoos,conditioners, serums, polysaccharide films, ointments, mousses, pomades,powders, bars, pencils, sprays, aerosols, capsules, gelatin capsules,soft capsules, hard capsules, tablets, sugar coated tablets, pills,powders, granules, chewing gum, solutions, suspensions, emulsions,syrups, elixirs, jellies and gelatins.
 8. The composition according toclaim 5, wherein this composition also comprises at least onecosmetically or pharmaceutically acceptable adjuvant selected from thegroup consisting of agents which inhibit neuronal exocytosis,anticholinergic agents, agents which inhibit muscular contraction,anti-aging agents, anti-wrinkle agents, antiperspirant agents,anti-inflammatory agents and/or analgesics, anti-itching agents, calmingagents, anesthetic agents, inhibitors of acetylcholine-receptoraggregation, agents that inhibit acetylcholinesterase, skin relaxantagents, melanin synthesis stimulating or inhibiting agents, whitening ordepigmenting agents, propigmenting agents, self-tanning agents,NO-synthase inhibiting agents, 5α-reductase inhibiting agents, lysyl-and/or prolyl hydroxylase inhibiting agents, antioxidants, free radicalscavengers and/or agents against atmospheric pollution, reactivecarbonyl species scavengers, anti-glycation agents, antihistamineagents, antiviral agents, antiparasitic agents, emulsifiers, emollients,organic solvents, liquid propellants, skin conditioners, humectants,substances that retain moisture, alpha hydroxy acids, beta hydroxyacids, moisturizers, epidermal hydrolytic enzymes, vitamins, aminoacids, proteins, pigments, colorants, dyes, biopolymers, gellingpolymers, thickeners, surfactants, softening agents, emulsifiers,binding agents, preservatives, agents able to reduce or treat bags underthe eyes, exfoliating agents, keratolytic agents, flaking agents,antimicrobial agents, antifungal agents, fungistatic agents,bactericidal agents, bacteriostatic agents, agents stimulating thesynthesis of dermal or epidermal macromolecules and/or capable ofinhibiting their degradation, collagen synthesis-stimulating agents,elastin synthesis-stimulation agents, decorin synthesis-stimulationagents, laminin synthesis-stimulation agents, defensinsynthesis-stimulating agents, chaperone synthesis-stimulating agents,cAMP synthesis-stimulating agents, AQP-3 modulating agents, aquaporinsynthesis modulating agents, proteins from the aquaporin family,hyaluronic acid synthesis-stimulating agents, glycosaminoglycansynthesis-stimulating agents, fibronectin synthesis-stimulating agents,sirtuin synthesis-stimulating agents, sirtuin activating agents, heatshock proteins, heat shock protein synthesis-stimulating agents, agentsstimulating the synthesis of lipids and components of the stratumcorneum, ceramides, fatty acids, agents that inhibit collagendegradation, matrix metalloproteinase inhibitory agents, agents thatinhibit elastin degradation, agents that inhibit serine proteases,agents stimulating fibroblast proliferation, agents stimulatingkeratinocyte proliferation, agents stimulating adipocyte proliferation,agents stimulating melanocyte proliferation, agents stimulatingkeratinocyte differentiation, agents stimulating or delaying adipocytedifferentiation, antihyperkeratosis agents, comedolytic agents,anti-psoriasis agents, DNA repair agents, DNA protecting agents,stabilizers, agents for the treatment and/or care of sensitive skin,firming agents, anti-stretch mark agents, binding agents, agentsregulating sebum production, lipolytic agents or agents stimulatinglipolysis, adipogenic agents, agents modulating PGC-1α expression,agents modulating PPARγ, agents which increase or reduce thetriglyceride content of adipocytes, anti-cellulite agents, agents whichinhibit the activity of PAR-2, agents stimulating healing, coadjuvanthealing agents, agents stimulating reepithelialization, coadjuvantreepithelialization agents, cytokine growth factors, agents acting oncapillary circulation and/or microcirculation, agents stimulatingangiogenesis, agents that inhibit vascular permeability, venotonicagents, agents acting on cell metabolism, agents to improvedermal-epidermal junction, agents inducing hair growth, hair growthinhibiting or retardant agents, hair loss retardant agents,preservatives, perfumes, cosmetic and/or absorbent and/or body odormasking deodorants, chelating agents, plant extracts, essential oils,marine extracts, agents obtained from a biotechnological process,mineral salts, cell extracts, sunscreens and organic or mineralphotoprotective agents active against ultraviolet A and/or B rays and/orinfrared A rays, and mixtures thereof.
 9. The compound according toclaim 1, wherein AA₁ is -Glu- AA₃ is -Leu-, AA₄ is -Lys-, AA₅ is -Arg-,and AA₆ is -Trp-.
 10. The compound according to claim 9, wherein AA₂ is-Glu- or -Asn-.
 11. The compound according to claim 1, wherein m+p+q issmaller than
 2. 12. The compound according to claim 1, wherein R₁ is notH and R₂ is not OH.
 13. A compound selected from R₁-(SEQ ID NO:116)-R₂and R₁-(SEQ ID NO:117)-R₂, stereoisomers thereof, mixtures thereofand/or cosmetically or pharmaceutically acceptable salts thereof,wherein: R₁ is selected from the group consisting of H, a polymerderived from polyethylene glycol, a non-cyclic substituted orunsubstituted aliphatic group, substituted or unsubstituted alicyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedheteroarylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted aralkyl and R₅—CO—, wherein R₅ is selected from the groupconsisting of H, a non-cyclic substituted or unsubstituted aliphaticgroup, substituted or unsubstituted alicyclyl, substituted orunsubstituted aryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heterocyclyl and substituted or unsubstitutedheteroarylalkyl; R₂ is selected from the group consisting of —NR₃R₄,—OR₃ and —SR₃ wherein R₃ and R₄ are independently selected from thegroup consisting of H, a polymer derived from polyethylene glycol, anon-cyclic substituted or unsubstituted aliphatic group, substituted orunsubstituted alicyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted heteroarylalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted aralkyl; wherein atleast one of: R₁ is not H, and R₂ is not OH; and R₁ and R₂ are notα-amino acids.
 14. The compound according to claim 13, wherein R₁ is notH and R₂ is not OH.
 15. The compound according to claim 13, wherein thecompound is selected from R₁-(SEQ ID NO:117)-R₂, stereoisomers thereof,mixtures thereof and/or cosmetically or pharmaceutically acceptablesalts thereof.